Primary Sulfonamides Research Articles

Synthesis, characterization, and antifungal activity of novel (Z)-N-(2-cyano-3-phenylprop-2-en-1-yl)-alkyl/aryl-sulfonamides derived from a Morita–Baylis–Hillman adduct

A series of allyl sulfonamides prepared from the reaction of the Morita–Baylis–Hillman adduct 2-[hydroxy(phenyl)methyl]acrylonitrile with primary sulfonamides (RSO2NH2), where R=C6H5 (1), 4-FC6H4 (2), 4-ClC6H4 (3), 4-BrC6H4 (4), 4-NO2C6H4 (5), CH3 (6), CH3CH2 (7), CH3(CH2)3 (8), and CH3(CH2)7 (9), were characterized by IR, 1H and 13C NMR spectroscopies, mass spectrometry and elemental analyses. BLYP/6-31G* calculations suggested stereoselective reactions, resulting in the exclusive formation of the thermodynamically more stable Z-products. The Z-configuration of the products was confirmed by NOE difference spectroscopy and single crystal X-ray diffraction measurements. The allyl sulfonamides were active against Colletotrichum gloeosporioides, an important agent of anthracnose in plants.

Natural Indian Natrolite zeolite-supported Cu nanoparticles: a new and reusable heterogeneous catalyst for N-arylation of sulfonamides with boronic acids in water under ligand-free conditions

We report here on the preparation of primary sulfonamides and efficient, easily recoverable and reusable copper nanoparticles supported on natural Indian Natrolite zeolite as a catalyst for arylation of sulfonamides with arylboronic acids in water. The catalyst was characterized using the powder XRD, SEM, EDS and FT-IR spectroscopy. The significant advantages of this methodology are high yields, elimination of organic solvents, and simple work-up procedure. The catalyst was easily isolated from the reaction mixture and reused with no significant loss in its activity.

Copper-Catalyzed Alkene Diamination: Synthesis of Chiral 2-Aminomethyl Indolines and Pyrrolidines.

Chiral vicinal diamines, including 2-aminomethyl indolines and pyrrolidines, are useful as ligands for catalytic asymmetric reactions and are also found as important components of bioactive compounds. Herein is reported the first copper-catalyzed alkene diamination that occurs with high enantioselectivity. The substrate range is the broadest yet reported for this kind of intra-/intermolecular reaction sequence both with respect to γ-alkenyl sulfonamide substrate and external amine nucleophile. The resulting products expand the availability of substituted 2-aminomethyl indolines and pyrrolidines, privileged compounds in asymmetric catalysis and medicinal chemistry. A unique solution to a challenging oxidation problem related to copper catalyst turnover is also presented.

A Prodrug Approach Toward Cancer-Related Carbonic Anhydrase Inhibition

The selective inhibition of cancer-associated human carbonic anhydrase (CA) enzymes, specifically CA IX and XII, has been validated as a mechanistically novel approach toward personalized cancer management. Herein we report the design and synthesis of a panel of 24 novel glycoconjugate primary sulfonamides that bind to the extracellular catalytic domain of CA IX and XII. These compounds were synthesized from variably acylated glycopyranosyl azides and either 3- or 4-ethynyl benzene sulfonamide using Cu(I)-catalyzed azide alkyne cycloaddition (CuAAC). The CA enzyme inhibition profile for all compounds was determined, while in vitro metabolic stability, plasma stability, and plasma protein binding for a representative set of compounds was measured. Our findings demonstrate the influence of the differing acyl groups on these key biopharmaceutical properties, confirming that acyl group protected carbohydrate-based sulfonamides have potential as prodrugs for selectively targeting the extracellular cancer-associated CA enzymes.

Antimalarial activity of compounds comprising a primary benzene sulfonamide fragment

Despite the urgent need for effective antimalarial drugs with novel modes of action no new chemical class of antimalarial drug has been approved for use since 1996. To address this, we have used a rational approach to investigate compounds comprising the primary benzene sulfonamide fragment as a potential new antimalarial chemotype. We report the in vitro activity against Plasmodium falciparum drug sensitive (3D7) and resistant (Dd2) parasites for a panel of fourteen primary benzene sulfonamide compounds. Our findings provide a platform to support the further evaluation of primary benzene sulfonamides as a new antimalarial chemotype, including the identification of the target of these compounds in the parasite.

Preparation of sulfonamides from N-silylamines

Sulfonamides have been prepared in high yields by the reactions of N-silylamines with sulfonyl chlorides and fluorides. In a competition experiment, the sulfonyl chlorides were found to be far more reactive than sulfonyl fluorides. The chemistry may be used to prepare aliphatic, aromatic, tertiary, secondary, and primary sulfonamides. It may also be done in the absence of solvent and the byproduct trimethylsilyl chloride recovered in good yield. Primary sulfonamides were synthesized from the sulfonyl chloride with aminotriphenyl silane (Ph3SiNH2), a conversion demonstrated with the synthesis of the carbonic anhydrase inhibitor, acetazolamide.

One-pot asymmetric synthesis of 2-aryl-2,3-dihydro-4-quinolones catalyzed by amino acid-derived sulfonamides

An organocatalyzed approach to the asymmetric synthesis of 2-aryl-2,3-dihydro-4-quinolones using amino-acid derived sulfonamides as organocatalysts, which can be easily prepared starting from l-proline, l-alanine, and l-phenylalanine, has been developed in high yields (up to 92%) and with moderate to good enantioselectivities (up to 74% ee). Additionally, opposite enantioselectivities for primary and secondary amino acid sulfonamides have also been observed.

Building a Sulfonamide Library by Eco-Friendly Flow Synthesis

A rapid and eco-friendly synthesis of a sulfonamide library under flow conditions is described. The study illustrates an efficient, safe, and easily scalable preparation of sulfonamides by use of a meso-reactor apparatus, thus demonstrating the impact of flow technologies within drug discovery. Waste minimization, employment of green media, and nontoxic reactants are achieved by the optimization of the flow setup and experimental protocol designed to sequentially synthesize primary, secondary, and tertiary sulfonamides. Isolation of the products involves only extraction and precipitation affording pure compounds in good to high yields without further purification for biological evaluation.

ChemInform Abstract: Copper‐Catalyzed N‐Arylation of Sulfonamides with Aryl Bromides under Mild Conditions.

This Letter describes a copper catalyzed sulfonamide coupling reaction with aryl bromides to form N-aryl sulfonamides under mild conditions, including the first examples of Cu-catalyzed sulfonamide coupling at room temperature. The reaction protocol tolerates a broad range of substrates including a variety of primary and secondary sulfonamides and challenging heteroaryl bromides such as 2-bromothiazole.

Secondary/tertiary benzenesulfonamides with inhibitory action against the cytosolic human carbonic anhydrase isoforms I and II

Carbonic anhydrase inhibitors of primary sulfonamide type, RSO2NH2, have clinical applications as diuretics, antiglaucoma, antiepileptic, antiobesity and antitumor drugs. Here we investigated inhibition of two human cytosolic isozymes, hCA I and II, with a series of secondary/tertiary sulfonamides, incorporating tosyl moieties (CH3C6H4SO2NR1R2). Most compounds inhibited both isoforms in low micromolar range, with inhibition constants between 0.181–6.01 μM against hCA I, and 0.209–0.779 μM against hCA II, respectively. These findings point out that substituted benzenesulfonamides may be used as leads for generating interesting CAIs probably possessing a distinct mechanism of action compared to primary sulfonamides. Indeed, classical RSO2NH2 inhibitors bind in deprotonated form to the Zn(II) ion from the CA active site and participate in many other favorable interactions with amino acid residues lining the cavity. The secondary/tertiary sulfonamides cannot bind to the zinc due to steric hindrance and probably are accommodated at the entrance of the active site, in coumarin binding-site.

N-Acyl DBN Tetraphenylborate Salts as N-Acylating Agents

Air-stable and crystalline N-acyl DBN tetraphenylborate salts have been synthesized from 1,5-diazabicyclo[4.3.0]non-5-ene (DBN) and the corresponding acyl chloride in the presence of sodium tetraphenylborate. The salts have been shown to be effective N-acylating agents, reacting with primary amines, secondary amines, and sulfonamides to form the corresponding N-acylated products in good yields. The DBN hydrotetraphenylborate byproduct can be conveniently removed by filtration, providing pure N-acylated products without the need for further purification. The N-acyl DBN tetraphenylborate salts are attractive alternatives to acyl halides as they can be stored in air without decomposition, avoid the production of free acid during acylation reactions, and can be used under more forcing thermal conditions.

Palladium-catalysed aminosulfonylation of aryl-, alkenyl- and heteroaryl halides: scope of the three-component synthesis of N-aminosulfonamides

By using DABCO·(SO(2))(2), DABSO, as a solid bench-stable SO(2)-equivalent, the palladium-catalysed aminosulfonylation of aryl-, alkenyl- and heteroaryl halides has been achieved. N,N-Dialkylhydrazines are employed as the N-nucleophiles and provide N-aminosulfonamides as the products in good to excellent yields. The reactions are operationally simple to perform, requiring only a slight excess of SO(2) (1.2-2.2 equiv.), and tolerate a variety of substituents on the halide coupling partner. Variation of the hydrazine component is also demonstrated. The use of N,N-dibenzylhydrazine as the N-nucleophile delivers N-aminosulfonamide products that can be converted into the corresponding primary sulfonamides using a high-yielding, telescoped, deprotection sequence. The ability to employ hydrazine·SO(2) complexes as both the N-nucleophile and SO(2) source is also illustrated.

Metal-free synthesis of allylic amines by cross-dehydrogenative-coupling of 1,3-diarylpropenes with anilines and amides under mild conditions

Dehydrogenative cross-coupling reaction of primary anilines, secondary anilines, carboxamides, and sulfonamides with 1,3-diarylpropenes to form a series of allylic amines promoted by DDQ have been realized. Both monoallylation and diallylation products can be selectively synthesized when primary anilines are used as the starting materials. The method may provide a wide scope of allylamines in scientific research including biologically active compound library construction.

Copper-catalyzed N-arylation of sulfonamides with aryl bromides under mild conditions

This Letter describes a copper catalyzed sulfonamide coupling reaction with aryl bromides to form N-aryl sulfonamides under mild conditions, including the first examples of Cu-catalyzed sulfonamide coupling at room temperature. The reaction protocol tolerates a broad range of substrates including a variety of primary and secondary sulfonamides and challenging heteroaryl bromides such as 2-bromothiazole.

ChemInform Abstract: A General Method for Palladium‐Catalyzed Reactions of Primary Sulfonamides with Aryl Nonaflates.

AbstractThe reaction allows an efficient access to a wide range of N‐aryl sulfonamides.

A General Method for Palladium-Catalyzed Reactions of Primary Sulfonamides with Aryl Nonaflates

A general method for Pd-catalyzed sulfonamidation of aryl nonafluorobutanesulfonates (aryl nonaflates) is described. A biaryl phosphine ligand, t-BuXPhos, formed the most active catalyst, and K(3)PO(4) in tert-amyl alcohol was found to be the optimal base-solvent combination for the reaction. The reaction conditions were tolerant of various functional groups such as cyano, nitro, ester, aldehyde, ketone, chloride, carbamate, and phenol. Heterocyclic aryl nonaflates were found to be suitable coupling partners. High yields of the coupled products were obtained from the reactions between inherently disfavored substrates such as electron-rich nonaflates and electron-poor sulfonamides. Kinetic data suggest reductive elimination to be the rate-limiting step for the reaction. The only limitation of this methodology that we have identified is the inability of 2,6-disubstituted aryl nonaflates to efficiently participate in the reaction.

Cobalt-catalyzed benzylic C–H amination via dehydrogenative-coupling reaction

An efficient direct benzylic C–H amination via dehydrogenative-coupling by using an inexpensive catalyst/oxidant (CoBr 2/ t BuOO t Bu) system is described. Various unmodified amides including primary or secondary sulfonamides, carboxamides, and carbamates preformed well with benzylic hydrocarbons with moderate to good yields.

ChemInform Abstract: Copper‐Catalyzed Amination of Primary Benzylic C—H Bonds with Primary and Secondary Sulfonamides.

AbstractThe amination of secondary benzylic C—H bonds is also possible.

ChemInform Abstract: Asymmetric Synthesis of α-Functionalized Primary Sulfonamides.

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Copper-Catalyzed Amination of Primary Benzylic C−H Bonds with Primary and Secondary Sulfonamides

A room-temperature, copper-catalyzed amination of primary benzylic C-H bonds with primary and secondary sulfonamides is described. The reaction is applicable to the coupling of a range of primary and secondary benzylic hydrocarbons with a diverse set of sulfonamides and is tolerant of substitution on both coupling partners. Factors which influence the selectivity of C-H functionalization between primary and secondary sites are examined.