N-sulfonyl Amidines Research Articles

An inexpensive, metal-free and one-pot approach towards N-sulfonyl amidines: Identification of a chorismate mutase inhibitor with activities against S. aureus

The simple yet innovative synthetic approaches for the direct access to the diversity based unique class of compounds of potential biological interest are of considerable interest as that can greatly facilitate the efforts in bioorganic / medicinal chemistry and drug discovery. In our efforts, we have developed a metal-free, inexpensive and one-pot method for the facile and direct synthesis of N-sulfonyl amidines that were designed as inhibitors of chorismate mutase. The methodology involved POCl3-SOCl2 promoted reaction of amide with sulphonamide to afford an array of new and unique class of compounds in good to acceptable yields. The methodology is free from the use of additional organic reaction media and amenable for scale-up. Based on in vitro and in silico studies, 3g has been identified as a first example of chorismate mutase inhibitor with selective and promising activities on a range of S. aureus strains. Indeed, the docking of 3g into AlphaFold predicted structure S. aureus CM I (UniProt ID: A0A380DU97) revealed good interactions with stabilization mostly via π-anion interactions in addition to a halogen (fluorine) bond. Compound 3g is of further pharmacological interest.

Copper-catalyzed the coupling reaction of sulfonylazides with formamides for the synthesis of N-sulfonyl amidines

A new strategy for copper-catalyzed the coupling reaction of sulfonylazides with formamides to construct a series of functionalized N-sulfonyl amidines in moderate to excellent yields has been established. Diazo reagent was applied as an important additive to activate formamides. This methodology was distinguished by operational simplicity, easily available starting materials and good functionality tolerance.

Olefin skeletal rearrangement enabling access to multiarylated N-sulfonyl amidines.

A base-promoted olefin skeletal rearrangement strategy from para-quinone methides (p-QMs) and N-fluoroarenesulfonamides is reported, enabling direct nitrogen insertion of olefins to produce a series of multiarylated (Z)-N-sulfonyl amidines with complete stereoselectivity and generally good yields. Using p-QMs without o-hydroxy substituents gave triarylated N-sulfonyl amidines, whereas tetraarylated N,N'-disulfonyl amidines were synthesized with the existence of o-hydroxy groups.

N-Sulfonyl amidine polypeptides: new polymeric biomaterials with conformation transition responsive to tumor acidity.

Manipulation of pH responsiveness is a frequently employed tactic in the formulation of trigger-responsive nanomaterials. It offers an avenue for "smart" designs capitalizing on distinctive pH gradients across diverse tissues and intracellular compartments. However, an overwhelming majority of documented functional groups (>80%) exhibit responsiveness solely to the heightened acidic milieu of intracellular pH (about 4.5-5.5). This scenario diverges markedly from the moderately acidic extracellular pH (∼6.8) characteristic of tumor microenvironments. Consequently, systems predicated upon intracellular pH responsiveness are unlikely to confer discernible advantages concerning targeted penetration and cellular uptake at tumor sites. In this study, we elucidated the extracellular pH responsiveness intrinsic to N-sulfonyl amidine (SAi), delineating a method to synthesize an array of SAi-bearing polypeptides (SAi-polypeptides). Notably, we demonstrated the pH-dependent modulation of SAi-polypeptide conformations, made possible by the protonation/deprotonation equilibrium of SAi in response to minute fluctuations in pH from physiological conditions to the extracellular milieu of tumors. This dynamic pH-triggered transition of SAi-polypeptides from negatively charged to neutrally charged side chains at the pH outside tumor cells (∼6.8) facilitated a transition from coil to helix conformations, concomitant with the induction of cellular internalization upon arrival at tumor sites. Furthermore, the progressive acidification of the intracellular environment expedited drug release, culminating in significantly enhanced site-specific chemotherapeutic efficacy compared with free-drug counterparts. The distinct pH-responsive attributes of SAi could aid the design of tumor acidity-responsive applications, thereby furnishing invaluable insights into the realm of smart material design.

Electrochemically Promoted Three-Component Reaction to N-Sulfonyl Amidines.

In this study, a multicomponent reaction via the Mannich intermediate was developed using methanol, secondary amine, and sulfonamide as starting materials. This method uses methanol as a green C1 source. The substrate scope is wide, and the yield is good. The mechanistic study shows that methanol generates formaldehyde under electrochemical conditions, and sulfonyl amidine as a nucleophile reacts with Schiff base intermediates to form N-sulfonyl amidine in a single step.

Phosphite-imidazole catalyzed N-formylation and N-acylation of amines.

A novel and convenient method for the N-formylation reaction of amines with DMF as a formylating agent has been developed, utilizing a catalytic amount of diethyl phosphite/imidazole. Diethyl phosphite, as a nucleophilic catalyst, plays a significant role in this conversion. The presented method has a broad substrate scope, and various N-formyl products were obtained in good to excellent yields. Moreover, by using DMA instead of DMF, the N-acetylation reaction was also successful. The reaction of o-phenylenediamines with DMF afforded the corresponding benzimidazoles. Furthermore, N-sulfonyl amidines were obtained in good to excellent yields by the reaction of sulfonamides with DMF under similar conditions.

Catalyst-free multicomponent polymerization of sulfonyl azide, aldehyde and cyclic amino acids toward zwitterionic and amphiphilic poly(N-sulfonyl amidine) as nanocatalyst precursor

Catalyst-free multicomponent polymerization of sulfonyl azide, aldehyde and cyclic amino acids toward zwitterionic and amphiphilic poly(N-sulfonyl amidine) as nanocatalyst precursor

Metal-Free Direct Access to N-Sulfonyl Amidines from Sulfonamides and Secondary Amines Involving Tandem C-N Bond Formations.

We report a mild and efficient metal-free one-pot procedure for the synthesis of N-sulfonyl amidines via the direct reaction of sulfonamides with secondary amines without using any additives. A wide range of substrates with variety of functional groups is well tolerated under the reaction conditions. Preliminary mechanistic studies indicate that the secondary amine plays a dual role as a C1 source of the amidine group and an aminating agent. Synthetic utility of this method is shown in the late-stage functionalization of drug molecules on the gram scale.

Copper-Catalyzed One-Pot Synthesis of N-Sulfonyl Amidines from Sulfonyl Hydrazine, Terminal Alkynes and Sulfonyl Azides.

N-Sulfonyl amidines are developed from a Cu-catalyzed three-component reaction from sulfonyl hydrazines, terminal alkynes and sulfonyl azides in toluene at room temperature. Particularly, the intermediate N-sulfonylketenimines was generated via a CuAAC/ring-opening procedure and took a nucleophilic addition with the weak nucleophile sulfonyl hydrazines. In addition, the stability of the product was tested by a HNMR spectrometer.

One-pot multicomponent synthesis of N-sulfonyl amidines using magnetic separable nanoparticles-decorated N-heterocyclic carbene complex with copper

Magnetic separable nanoparticles-decorated N-heterocyclic carbene complex with copper (MNP[1-Methyl benzimidazole]NHC@Cu) has been prepared by covalent grafting of ionic liquid like 1-methyl benzimidazole unit on the surface of chlorofunctionalized Fe3O4 magnetic nanoparticles (MNPs) followed by metallation with copper(I) iodide. MNP[1-Methyl benzimidazole]NHC@Cu complex has been characterized by different techniques including Fourier transform infrared (FT-IR) spectroscopy, thermogravimetric analysis (TGA), energy-dispersive X-ray (EDX) analysis, X-ray diffraction (XRD), transmission electron microscopy (TEM) and vibrating sample magnetometer (VSM). MNP[1-Methyl benzimidazole]NHC@Cu complex was successfully implemented as heterogeneous catalyst in one-pot multicomponent synthesis of N-sulfonyl amidines from phenylacetylene, tosyl azide and amines at room temperature. Complex could be recycled six times without significant loss in the yield of product.

Sulfonylimination of Proline with Sulfonylazides Involving Aldehyde-Induced Decarboxylation Coupling.

In the presence of aldehyde, a facile method was developed to obtain N-sulfonyl amidines under metal- and oxidant-free conditions by the decarboxylative of proline. This transformation features a double C-N bond formation and allows for the green synthesis of the N-sulfonyl amidines on the basis of mild conditions.

Regioselective synthesis of heterocyclic N-sulfonyl amidines from heteroaromatic thioamides and sulfonyl azides.

N-Sulfonyl amidines bearing 1,2,3-triazole, isoxazole, thiazole and pyridine substituents were successfully prepared for the first time by reactions of primary, secondary and tertiary heterocyclic thioamides with alkyl- and arylsulfonyl azides. For each type of thioamides a reliable procedure to prepare N-sulfonyl amidines in good yields was found. Reactions of 1-aryl-1,2,3-triazole-4-carbothioamides with azides were shown to be accompanied with a Dimroth rearrangement to form 1-unsubstituted 5-arylamino-1,2,3-triazole-4-N-sulfonylcarbimidamides. 2,5-Dithiocarbamoylpyridine reacts with sulfonyl azides to form a pyridine bearing two sulfonyl amidine groups.

Transition metal- and catalyst-free one-pot green method for the synthesis of N-sulfonyl amidines via direct reaction of sulfonyl azides with amines.

In this report, a green synthesis of N-sulfonyl amidines via the direct reaction of tertiary or secondary amines with sulfonyl azides is described. Transition metal- and catalyst-free conditions were used for the synthesis of biologically important N-sulfonyl amidines. Further studies showed that the reaction proceeded via in situ aerobic oxidation of amines under reflux conditions.

AN EFFICIENT METHOD FOR THE SYNTHESIS OF 2-THIAZOLEACETIC ACID N -SULFONYL AMIDINES

A three-step method was designed and developed on the basis of retrosynthetic analysis for the synthesis of hybrid molecules containing a thiazole ring and an N-sulfonyl amidine fragment, connected by a methylene linker. The mechanism of the last step involves the formation of intermediate 1,2,3,4-thiatriazoles and their transformation into the final products as a result of the elimination of molecular nitrogen and sulfur.

An efficient method for the synthesis of 2-thiazoleacetic acid N-sulfonyl amidines

A three-step method was designed and developed on the basis of retrosynthetic analysis for the synthesis of hybrid molecules containing a thiazole ring and an N-sulfonyl amidine fragment, connected by a methylene linker. The mechanism of the last step involves the formation of intermediate 1,2,3,4-thiatriazoles and their transformation into the final products as a result of the elimination of molecular nitrogen and sulfur.

Three component reaction of aryl diazonium salt with sulfonamide & actonitrile to synthesize N-sulfonyl amidine

A new method was developed to prepare N-sulfonyl amidine compounds through three-component reaction of aryl diazonium salts with sulfonamides and acetonitrile, in which, nitrilium ion intermediate, generated from the reaction of aryldiazonium salt with nitrile, was subsequently trapped by sulfonamides. A series of N-sulfonyl amidine derivatives were synthesized by using various types of aryl diazonium salts, sulfonamides and nitriles. In addition, indolyl imine products could also be prepared by using indole as the nucleophile to trap nitrilium ion intermediate.

N-Sulfonyl acetylketenimine as a highly reactive intermediate for the synthesis of N-sulfonyl amidines.

A highly reactive intermediate N-sulfonyl acetylketenimine was generated from a 3-butyn-2-one participating CuAAC/ring-opening method. Its high reactivity due to bearing two EWGs allowed us to offer the first example of a reaction between ketenimine and amide to synthesize N-sulfonyl amidines efficiently.

Synthesis of N-Sulfonyl Amidines and Acyl Sulfonyl Ureas from Sulfonyl Azides, Carbon Monoxide, and Amides.

A Pd-catalyzed and ligand-free carbonylation/cycloaddition/decarboxylation cascade synthesis of sulfonyl amidines from sulfonyl azides and substituted amides at low CO pressure is reported. The reaction proceeds via an initial Pd-catalyzed carbonylative generation of sulfonyl isocyanates from sulfonyl azides, followed by a [2 + 2] cycloaddition with amides and subsequent decarboxylation, which liberates the desired sulfonyl amidines, generating N2 and CO2 as the only reaction byproducts. Using this simple protocol, a diverse range of sulfonyl amidines was obtained in moderate to excellent yields. In addition, the reaction can also be directed through a more conventional amidocarbonylation pathway by employing N-monosubstituted amide nucleophiles to afford acyl sulfonyl ureas in good yields.

Galactose-amidine derivatives as selective antagonists of galectin-9

The family of galectin proteins involved in adhesion, growth regulation, immunity, and inflammatory events are important targets for development of small molecule antagonists. Here, N-sulfonyl amidine galactopyranoside derivatives obtained via a multicomponent reaction between galactose alkyne derivatives, sulfonyl azides, and amines were evaluated as antagonists of galectin-1, -2, -3, -4N (N-terminal domain), -4C (C-terminal domain), -8N, -9N, and -9C in a competitive fluorescence polarization assay. Highly selective compounds against galectin-9N with up to 30-fold improved affinity compared to the reference methyl β-d-galactopyranoside were identified. Molecular dynamics simulation suggested that the selectivity and affinity for galectin-9N originate from the N-sulfonyl amidine moieties forming tridentate hydrogen bonds to two asparagine side chains and one phenyl stacking edge-to-face to an arginine side chain. These selective galectin-9N antagonists are of significant value as chemical tools for studying galectin-9 biology and chemistry as well as possible starting structures for the discovery of galectin-9-targeting drugs influencing, e.g., immune regulation.

N-Sulfonyl amidine synthesis via three-component coupling reaction using heterogeneous copper catalyst derived from metal-organic frameworks

Three-component coupling reaction of terminal alkyne, sulfonyl azide, and amine for the synthesis of N-sulfonyl amidine was developed using heterogeneous Cu@C catalyst, which was generated by pyrolysis of HKUST-1 (Cu3(BTC)2, BTC=1,3,5-benzenetricarboxylate). A variety of terminal alkynes, sulfonyl azides, and amines underwent three-component coupling in the presence of 5mol% Cu@C. The used Cu@C catalyst was readily separated by centrifugation and could be reused at least three times with no loss of reactivity. Filtration experiments revealed that the developed Cu@C catalysis is basically heterogeneous.