Phosphoryl Azide Research Articles

Ruthenium-catalysed direct C-H amidation of 4-aryl-pyrrolo[2,3-d]pyrimidines with acyl/phosphoryl azides.

A ruthenium-catalysed arene ortho C-H amidation of 4-aryl-pyrrolo[2,3-d]pyrimidine derivatives with acyl azides or phosphoryl azides as the nitrogen sources toward C-N bond formation was developed. This protocol could offer a novel and direct approach to access a series of amidated and phosphoramidated pyrrolo[2,3-d]pyrimidine derivatives in moderate to good yields, thereby evading the general Curtius rearrangement. The protocol features significant functional group tolerance and a single-step process, with the release of only innocuous molecular nitrogen as the byproduct.

Recent advances in metal directed C-H amidation/amination using sulfonyl azides and phosphoryl azides.

Transition metal-catalyzed C-N bond formation reactions have gained popularity as a method for selectively transforming common C-H bonds into N-functionalized molecules. This approach is particularly useful for synthesizing aminated molecules, which require aminating reagents and amidated building blocks. Over the past two decades, significant advancements have been achieved in transition-metal-catalyzed C-H functionalization, with organic azides emerging as promising amino sources and internal oxidants. This review focuses on recent developments in utilizing sulfonyl and phosphoryl azides as building blocks for directed intra- and intermolecular C-H functionalization reactions. Specifically, it discusses methods for synthesizing sulfonamidates and phosphoramidates using sulfonyl and phosphoryl azides, respectively. The article highlights the potential of C-H functionalization reactions with organic azides for efficiently and sustainably synthesizing N-functionalized molecules, providing valuable insights into the latest advancements in this field.

Characterizing Three Azides for Their Potential Use as C. elegans Anesthetics.

Sodium azide (NaN 3 ) is widely used as an anesthetic in the C. elegans community for studying animal behavior. It is not known whether other azides can function as anesthetics. This is quite important for the C. elegans labs in which NaN 3 is not a convenient choice, such as all the labs located in China, where NaN 3 is under tight regulation, and alternative anesthetics need to be characterized. In the present study, we focused on another three azides, potassium azide (KN 3 ), trimethylsilyl azide (TMSA), and diphenyl phosphoryl azide (DPPA), which are not regulated in China. We characterized their performance in chemotactic behavioral assays and buffer-based assays. Our results suggest that KN 3 can immobilize worms as effectively as NaN 3 in the above-mentioned assays. Therefore, we recommend KN 3 as a routine anesthetic for C. elegans labs.

Frustrated Lewis Pair Stabilized Phosphoryl Nitride (NPO), a Monophosphorus Analogue of Nitrous Oxide (N2O).

Phosphoryl nitride (NPO) is a highly reactive intermediate, and its chemistry has only been explored under matrix isolation conditions so far. Here we report the synthesis of an anthracene (A) and phosphoryl azide based molecule (N3P(O)A) that acts as a molecular synthon of NPO. Experimentally, N3P(O)A dissociates thermally with a first-order kinetic half-life that is associated with an activation enthalpy of ΔH⧧ = 27.5 ± 0.3 kcal mol-1 and an activation entropy of ΔS⧧ = 10.6 ± 0.3 cal mol-1 K-1 that are in good agreement with calculated DLPNO-CCSD(T)/cc-pVTZ//PBE0-D3(BJ)/cc-pVTZ energies. In solution N3P(O)A undergoes Staudinger reactivity with tricyclohexylphosphine (PCy3) and subsequent complexation with tris(pentafluorophenyl)borane (B(C6F5)3, BCF) to form Cy3P-NP(A)O-B(C6F5)3. Anthracene is cleaved off photochemically to form the frustrated Lewis pair (FLP) stabilized NPO complex Cy3P⊕-N═P-O-B⊖(C6F5)3. An intrinsic bond orbital (IBO) analysis suggests that the adduct is zwitterionic, with a positive and negative charge localized on the complexing Cy3P and BCF, respectively.

Substitution of diarylphosphoryl azides with aliphatic amines catalyzed by simple rare‐earth metal salts: Efficient and novel preparation of phosphoryl amides

AbstractA novel and high efficient protocol was disclosed herein for the rare‐earth metal salt‐catalyzed substitution of phosphoryl azides with amines. In this homogeneous catalysis system, different diarylphosphoryl azides and aliphatic and aromatic amines were evaluated under the optimized reaction conditions, and a series of phosphoryl amides were generated through LaCl3 catalysis for the first time in moderate to excellent isolated yields. Different from well‐tolerated phosphoryl azide substrates, the amino nucleophiles, however, were mainly limited to primary amines; their secondary analogues or anilines were reluctant to experience desired transformations. Nevertheless, this methodology has proven to be a simple, practical, and scalable application of the promising lanthanide catalyst toward the exiting methodology library to prepare phosphoryl amides.

A Click Reaction Enabled by Phosphorus‐Oxygen Bond for Synthesis of Triazoles

AbstractSynthesis of various N−H triazoles via azidyl radical was achieved using diphenyl phosphoryl azide (DPPA) and internal alkynes containing carbonyl group in wet‐DMSO at 90 °C in excellent yield. Mechanistic investigations revealed that an azidyl radical was generated in the reaction medium. The driving force was probably due to the presence of the C=O group of ester or ketone in conjugation with the triple bond of the substrate. This resulted in cleavage of the phosphorus nitrogen (P−N) bond of DPPA by forming an allenic intermediate. The C=O group of the ester or ketone is a determinant factor that results in triazole as the outcome. The formation of the phosphorus oxygen bond resulted in cleavage of a strong P−N bond (617.1±20.9 kJ mol−1) of phosphoryl azidate in an additive free Click reaction of internal alkynes. Overall, good to excellent yield of N1‐H triazole scaffolds were synthesized following the protocol.

DNA-binding and Kinetics AChE Inhibition studies of Cobalt(II) and Copper(II) Complexes Derived from 5-[4-(dimethylamino) phenyl]-3-(2-oxo-2H-chromen-3-yl)-1H-pyrazole-1-carbothioamide

A series of transition metal complexes of the general formula [MLCl(H2O)2] ,M=Co(II) and Cu(II) and L=3-(pyridine-2-yl)-4,5-dihydro-1H-pyrazole-1-thiocarboxamides (L) have been synthesized by a two steps reaction sequence starting from substituted Benz aldehydes and 2-acetyl pyridine. The cobalt(II) and copper(II) complexes were isolated in their solid state by the direct reactions of ligand ,L with CoCl2.6H2O and CuCl2•2H2O solutions. The structure and geometry of the metal complexes were determined their chemical structures on the basis of (CHNS) elemental analyses, FT-IR,LC-MS and UV-Visible spectra beside the measurements of magnetic susceptibility at room temperature and molar conductance in DMSO solvent. The application part of the recent paper was the screening of the new poly dentate-based pyrazoline ligand and its CoL and CuL complexes with thymus DNA act as powerful sequence-specific gene modulators, by exerting their effect from transcription regulation to gene modification. The DNA binding abilities of the 5-[4-(dimethylamino)phenyl]-3-(2-oxo-2H-chromen-3-yl)-1H-pyrazole-1-carbithioamide and it Cu , Co complexes was evaluated by UV–Vis titration experiments, which was a useful method to calculate the DNA binding constants in vitro. After Calf Thymus DNA (CT DNA) was added to the phosphate buffer solution containing constant ligand and complexes concentrations, all of the solutions exhibited a slight hypochromic without any significant spectral shift. The binding constants of the compounds were calculated by using a plot of D/∆Ɛapp versus D. Close ,Cu and Co showed the largest binding constant (7.8 * 104 , 8 * 108 , 6.1* 103 ) M for binding with DNA respectively . Specifically, both compounds showed hypochromicity upon increasing DNA concentration, indicating that both compounds interacted with the DNA helix. However, a weak hypochromic effect is indeed observed, and no red shift is apparent. In a third part of study ,a series of chromene and its complexes with Co and Cu were synthesized and their acetyl cholinesterase enzyme (AChE) inhibitory effects were investigated. All carben were synthesized from the corresponding carboxylic acids via of the acids with diphenyl phosphoryl azide followed by addition of benzyl alcohol. The chromene and its complexes with Co and Cu were determined to be very good inhibitors against for AChE with different type of inhibition (mix and non-competitive) inhibition.

Iridium Catalyzed C—H Amidation of Benzamides with Phosphoryl Azides in Ionic Liquids

Iridium Catalyzed C—H Amidation of Benzamides with Phosphoryl Azides in Ionic Liquids

Recyclable copper catalyst on chitosan for facile preparation of alkyl/aryl mixed phosphates via deaminated esterification between diphenylphosphoryl azides and aliphatic alcohols

An efficient methodology was established for the preparation of alkyl/aryl mixed phosphates under aerobic conditions promoted by a easily recoverable heterogeneous catalyst. This highly active copper catalyst was obtained by directly mixing of copper precursor with chitosan solution, followed by a simple work-up process. In this catalytic system, different phosphoryl azides and aliphatic alcohols were employed to generate desired products in moderate to excellent yields with good functional group tolerance. This protocol provided a practical application of the chitosan supported heterogeneous copper catalyst towards a novel PO bond formation.

Electrophilic Azides for Materials Synthesis and Chemical Biology.

Organic azides are involved in a variety of useful transformations, including nitrene chemistry, reactions with nucleophiles and electrophiles, and cycloadditions. The 1,3-dipolar cycloadditions of azides constitute a major class of highly reliable and versatile reactions, as shown by the development and rapid adoption of click chemistry and bioorthogonal chemistry. Metal-catalyzed azide-alkyne cycloaddition (Cu/RuAAC), the prototypical click reaction, has found wide utility in pharmaceutical, biomedical, and materials sciences. The strain-promoted, or distortion-accelerated, azide-alkyne cycloaddition eliminates the need for a metal catalyst.In the azide-mediated 1,3-dipolar cycloaddition reactions, azides are ambiphilic, i.e., HOMO-LUMO-controlled dipoles where both the HOMO and LUMO interact strongly with the dipolarophile. Azide-alkyne cycloaddition proceeds primarily through the HOMOazide-LUMOdipolarophile interaction, and electron-deficient dipolarophiles react more readily. The inverse-electron-demand reaction, involving the LUMOazide-HOMOdipolarophile interaction, is less common because of the low stability of electron-deficient azides such as acyl, sulfonyl, and phosphoryl azides. Nevertheless, there have been reports since the 1960s showing enhanced reaction kinetics between electron-poor azides and electron-rich dipolarophiles. Our laboratory has developed the use of perfluoroaryl azides (PFAAs), a class of stable electron-deficient azides, as nitrene precursors and for reactions with nucleophiles and electron-rich dipolarophiles. Perfluorination on the aryl ring also facilitates the synthesis of PFAAs and quantitative analysis of the products by 19F NMR spectroscopy.In this Account, we summarize key reactions involving electrophilic azides and applications of these reactions in materials synthesis and chemical biology. These electron-deficient azides exhibit unique reactivity toward nucleophiles and electron-rich or strained dipolarophiles, in some cases leading to new transformations that do not require any catalysts or products that are impossible to obtain from the nonelectrophilic azides. We highlight work from our laboratories on reactions of PFAAs with enamines, enolates, thioacids, and phosphines. In the reactions of PFAAs with enamines or enolates, the triazole or triazoline cycloaddition products undergo further rearrangement to give amidines or amides as the final products at rates of up to 105 times faster than their non-fluorinated anlogues. Computational investigations by the distortion/interaction activation strain model reveal that perfluorination lowers the LUMO of the aryl azide as well as the overall activation energy of the reaction by decreasing the distortion energies of the reactants to reach the transition states. The PFAA-enamine reaction can be carried out in a one-pot fashion using readily available starting materials of aldehyde and amine, making the reaction especially attractive, for example, in the functionalization of nanomaterials and derivatization of antibiotics for the preparation of theranostic nanodrugs. Similar fast kinetics was also observed for the PPAA-mediated Staudinger reaction, which proceeds at 104 times higher rate than the classic Staudinger ligation, giving stable phosphoimines in high yields. The reaction is biorthogonal, allowing cell-surface labeling with minimal background noise.

Copper catalyzed synthesis of aryl/alkyl mixed phosphates from diphenylphosphoryl azides and aliphatic alcohols under mild conditions

An efficient and convenient one-pot protocol is developed to prepare aryl/alkyl mixed phosphates in the presence of copper catalyst under exceptionally mild conditions. A series of versatile, ubiquitous, and inexpensive phosphoryl azides and aliphatic alcohols are combined for the first time ever. Diphenylphosphoryl azide is employed as novel phosphors reagent through an unexpected cleavage of PN bond. The transformation is advantageous with respect to a broad of functional group compatibility and different esterification products are isolated in good to excellent results. This new catalytic system represents a superior platform towards a mild, operationally simple, practical, and scalability alternative to access target molecules. Furthermore, a plausible mechanism is proposed based on insightful mechanistic studies.

Transition-metal-free amination phosphoryl azide for the synthesis of phosphoramidates.

A facile and efficient approach to phosphoramidates was developed via amination of phosphoryl azides. A variety of phosphoramidates were obtained in one step with good to excellent yields under a mild reaction system. The process uses easily available amines as a N source and offers a new opportunity for P–N bond formation.

Production and Characterization of Chemically Cross-Linked Collagen Scaffolds.

Chemical cross-linking of collagen-based devices is used as a means of increasing the mechanical stability and control the degradation rate upon implantation. Herein, we describe techniques to produce cross-linked with glutaraldehyde (GTA; amine terminal cross-linker), 4-arm polyethylene glycol succinimidyl glutarate (4SP; amine terminal cross-linker), diphenyl phosphoryl azide (DPPA; carboxyl terminal cross-linker), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC; carboxyl terminal cross-linker) collagen films. In addition, we provide protocols to characterize the biophysical (swelling), biomechanical (tensile), and biological (metabolic activity, proliferation and viability using human dermal fibroblasts and THP-1 macrophages) properties of the cross-linked collagen scaffolds.

Copper(II)-Catalyzed Reactions of α-Keto Thioesters with Azides via C-C and C-S Bond Cleavages: Synthesis of N-Acylureas and Amides.

Cu(II)-catalyzed reaction of α-keto thioesters with trimethylsilyl azide (TMSN3) proceeds with the transformation of the thioester group into urea through C-C and C-S bond cleavages, constituting a practical and straightforward synthesis of N-acylureas. When diphenyl phosphoryl azide (DPPA) is used instead as the azide source in an aqueous environment, primary amides are formed via substitution of the thioester group. The reactions are proposed to proceed through Curtius rearrangement of the initially formed α-keto acyl azide to generate an acyl isocyanate intermediate, which reacts further with an additional amount of azide or water and rearranges to afford the corresponding products. To demonstrate the potentiality of the method, one-step syntheses of pivaloylurea and isovaleroylurea, displaying anticonvulsant activities, have been carried out.

Iridium-catalyzed C-H phosphoramidation of N-aryl-7-azaindoles with phosphoryl azides.

An iridium-catalyzed C-H phosphoramidation of N-aryl-7-azaindoles with phosphoryl azides was developed, affording a series of 7-azaindole phenylphosphoramidates in moderate to good yields. This protocol displays good functional group tolerance, which offers a novel and direct approach to access 7-azaindole phenylphosphoramidates.

Nile tilapia skin collagen sponge modified with chemical cross-linkers as a biomedical hemostatic material

Nile tilapia skin collagen sponges were fabricated by freeze-drying technology and modified with 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide in the presence of N-hydroxysuccinimide (EDC/NHS), genipin+PBS, genipin+ethanol, tea polyphenol (TP), nordihydroguaiaretic acid (NDGA) and diphenyl phosphoryl azide (DPPA). Physicochemical and biological properties, micromorphology and compatibility before and after modification were investigated to evaluate collagen sponge as a hemostatic biomedical material. The mechanical property of collagen sponges strengthened after cross-linking. The elongation at break of cross-linked collagen sponges decreased except for EDC/NHS, which was close to that of non-crosslinked. The collagen sponge cross-linked with EDC/NHS exhibited the highest hygroscopicity in comparison with other cross-linkers. The resistance to collagenase biodegradation of collagen sponges after cross-linking strengthened significantly except for NDGA. Collagen sponges cross-linked with EDC/NHS, TP and NDGA maintained high porosity (97–98%), similar to non-crosslinked (98.42%). Collagen sponges could shorten the blood coagulation time. From the variations of the FTIR spectrum pattern and SEM, DPPA could change the secondary structure of collagen and destroy the spongy structure of collagen sponge, which was not suitable for the cross-linking of collagen sponge. Whereas, EDC/NHS was recognized as a perfect cross-linker owing to its excellent properties and porous microstructure. All fabricated collagen sponges were recognized to be biocompatible by the hemolysis assay in vitro. Therefore, collagen sponge modified with EDC/NHS could be used as a perfect biomedical hemostatic material.

Improved synthesis of glycine, taurine and sulfate conjugated bile acids as reference compounds and internal standards for ESI–MS/MS urinary profiling of inborn errors of bile acid synthesis

Bile acid synthesis defects are rare genetic disorders characterized by a failure to produce normal bile acids (BAs), and by an accumulation of unusual and intermediary cholanoids. Measurements of cholanoids in urine samples by mass spectrometry are a gold standard for the diagnosis of these diseases. In this work improved methods for the chemical synthesis of 30 BAs conjugated with glycine, taurine and sulfate were developed.Diethyl phosphorocyanidate (DEPC) and diphenyl phosphoryl azide (DPPA) were used as coupling reagents for glycine and taurine conjugation. Sulfated BAs were obtained by sulfur trioxide-triethylamine complex (SO3-TEA) as sulfating agent and thereafter conjugated with glycine and taurine. All products were characterized by NMR, IR spectroscopy and high resolution mass spectrometry (HRMS). The use of these compounds as internal standards allows an improved accuracy of both identification and quantification of urinary bile acids.

Synthesis and inhibitory properties of some carbamates on carbonic anhydrase and acetylcholine esterase

A series of carbamate derivatives were synthesized and their carbonic anhydrase I and II isoenzymes and acetylcholinesterase enzyme (AChE) inhibitory effects were investigated. All carbamates were synthesized from the corresponding carboxylic acids via the Curtius reactions of the acids with diphenyl phosphoryl azide followed by addition of benzyl alcohol. The carbamates were determined to be very good inhibitors against for AChE and hCA I, and II isoenzymes. AChE inhibition was determined in the range 0.209–0.291 nM. On the other hand, tacrine, which is used in the treatment of Alzheimer’s disease possessed lower inhibition effect (Ki: 0.398 nM). Also, hCA I and II isoenzymes were effectively inhibited by the carbamates, with inhibition constants (Ki) in the range of 4.49–5.61 nM for hCA I, and 4.94–7.66 nM for hCA II, respectively. Acetazolamide, which was clinically used carbonic anhydrase (CA) inhibitor demonstrated Ki values of 281.33 nM for hCA I and 9.07 nM for hCA II. The results clearly showed that AChE and both CA isoenzymes were effectively inhibited by carbamates at the low nanomolar levels.

ChemInform Abstract: Iridium‐Catalyzed Phosphoramidation of Arene C—H Bonds with Phosphoryl Azide.

Abstract33 examples

Synthesis of 1,2-dihydro-2-oxo-4-quinolinyl phosphates from 2-acyl-benzoic acids

We report a facile synthesis of 1,2-dihydro-2-oxo-4-quinolinyl phosphates (1a–l) starting from 2-acyl-benzoic acids (2a–l) in the presence of phosphoryl azides via a one-pot cascade reaction involving a Curtius rearrangement, an intramolecular nucleophilic addition of the enol carbon to the isocyanate intermediate, and an addition-elimination of the enol oxygen to the phosphoryl azide. During the reaction three new bonds are formed under mild conditions to yield 1,2-dihydro-2-oxo-4-quinolinyl phosphates in modest yields.