Iridium‐Catalyzed H/D Exchange: Ligand Complexes with Improved Efficiency and Scope

Hydrogen isotope exchange (HIE) is one of the most attractive tools for the introduction of deuterium or tritium to an organic compound. Herein, iridium complexes with N,P‐ligands, highly active catalysts for asymmetric double bond reductions, have been tested for their HIE capabilities. Electron‐rich ligands, containing dicyclohexylphosphines or phosphinites, have been identified as excellent ligands for efficient deuterium incorporation. Substrates with strong directing groups, that is, pyridines, ketones, and amides, as well as weak ligating units, such as, nitro, sulfones, and sulfonamides, could be labeled efficiently. With the addition of tris(pentafluorophenyl) borane to the reaction mixture, also highly deactivating nitrile substituents were well tolerated in the reaction. Based on the excellent results obtained with the chiral ThrePhox ligand, a structurally simpler, achiral ligand was developed. The iridium complex containing this ligand, proved to be a powerful catalyst for HIE reactions.     

A reversible safety-catch method for the hydrogenolysis of N-benzyl moieties

The benzyl groups of β-hydroxy-N-benzyl sulfonamides are labile toward hydrogenolysis-unlike N-benzyl sulfonamides lacking the β-hydroxy moiety. We find that N-acyl-N-benzyl sulfonamides undergo hydrogenolysis under very mild conditions. Based upon these observations, we developed a reversible safety-catch method using tert-butoxycarbonyl moieties to activate N-benzyl sulfonamides toward hydrogenolysis. We also explored the utility of the safety-catch activation method for other nitrogen-based functionality such as N-benzyl carboxamides, imides, and related functionality.     

Practical preparation of N-(1-alkynyl)sulfonamides and their synthetic utility in titanium alkoxide-mediated coupling reactions

Aliphatic and aromatic sulfonamides were alkynylated with 1-bromo-1-alkynes in the catalytic presence of CuI to give N-(1-alkynyl)sulfonamides in good to excellent yields. Racemization of optically active sulfonamides was not observed during this alkynylation. The acetylene-titanium complexes generated from the resultant N-(1-alkynyl)sulfonamides and Ti(O-i-Pr)₄/2 i-PrMgCl underwent regio-, olefinic stereo-, and diastereoselective addition to aldehydes to give virtually single allyl alcohols. Alternatively, inter- or intramolecular coupling reaction between N-(1-alkynyl)sulfonamides and another acetylene or olefin with the above titanium alkoxide reagent generated the corresponding titanacycles, hydrolysis of which furnished stereo-defined (sulfonylamino)dienes or cyclic compounds.     

Ruthenium trichloride catalyzed synthesis of 2,3-unsaturated-N-glycosides via Ferrier azaglycosylation

An efficient, economical and mild protocol for the synthesis of 2,3-unsaturated-N-glycosides has been developed using ruthenium(III) chloride. The Ferrier azaglycosylation of glycals with various N-nucleophiles such as sulfonamides, benzamides, carbamates and N-substituted sulfonamides proceeded smoothly to afford the corresponding 2,3-unsaturated-N-glycosides or ‘N-pseudoglycals’ in good yields (64–98%). High α-anomeric selectivity was observed with N-substituted sulfonamides such as N-benzyl or N-phenyl sulfonamides under similar conditions.     

Boron trichloride as an efficient and selective agent for deprotection of tert-butyl aryl sulfonamides

A fast, mild and selective method for deprotection of tert-butyl aryl sulfonamides utilizing BCl₃ as deprotection reagent has been developed. A variety of tert-butyl aryl sulfonamides used under these conditions gave the corresponding primary sulfonamides in high yields. The method does not cleave methoxy groups and prevents incorporation of tert-butyl groups onto electron-rich aromatic rings.     

Ionic liquid enabled sulfamoylation of arenes: an ambient, expeditious and regioselective protocol for aryl sulfonamides

The ionic liquid, 1-butyl-3-methylimidazolium chloroaluminate, [bmim]Cl·AlCl₃, N=0.67 mediated syntheses of aromatic sulfonamides via electrophilic substitution of arenes is reported. The protocol serves as a distinctly expeditious and ambient route towards the syntheses of these pharmaceutically useful compounds, yielding quantitative conversions at room temperature within 5-30 min in most of the cases. The Lewis acidity and molar stoichiometry of the ionic liquid influences the extent of conversion. The method has been used for the syntheses of a diverse range of sulfonamides by variation of arenes and sulfamoyl chlorides. With monosubstituted benzenes, the protocol offers an added advantage of exclusive selectivity towards the formation of para substituted sulfonamides over the ortho products.     

Practical acid-catalyzed acylation of sulfonamides with carboxylic acid anhydrides

A highly efficient reaction between sterically and electronically diverse sulfonamides and carboxylic acid anhydrides to furnish monoacylated N-acylsulfonamides is described. This represents the first systematic disclosure of the scope of sulfuric acid-catalyzed acylation of sulfonamides.     

Facile synthesis of acyclic azanucleosides from N-pivaloyloxymethyl amides and sulfonamides: synthesis of aza-analogues of Ganciclovir

N-Pivaloyloxymethyl amides and sulfonamides, readily available from N-alkylation of both amides and sulfonamides with commercial chloromethyl pivaloate, were converted into acyclic azanucleosides via a one-pot base silylation/nucleoside coupling procedure.     

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.     

Elimination of benzotriazolyl group in N-(α-benzotriazol-1-ylalkyl)amides and N-(α-benzotriazol-1-ylalkyl)sulfonamides: their self-coupling and cross-coupling reactions with carbonyl compounds

The elimination of benzotriazolyl group from N-(α-benzotriazol-1-ylalkyl)amides and N-(α-benzotriazol-1-ylalkyl)sulfonamides are readily realized with samarium diiodide as a reducing agent. The resulting intermediates undergo a dimerization or cross-coupling reaction with carbonyl compounds, thus affording the corresponding dimers or α-hydroxyalkylated sulfonamides in moderate yields.     

Studies concerning the double reduction of Diels-Alder derived bicylic sulfonamides

A series of bicyclic sulfonamides, 14-17, was prepared by thermal, intramolecular Diels-Alder cycloaddition. The ratio of exo:endo-diastereoisomers formed following this process was found to be dependent on the substitution pattern of the dienophile. Styryl substituted sulfonamides preferentially formed the corresponding exo-adducts, whereas vinyl substituted sulfonamides preferentially gave the endo-adducts. These adducts were treated under dissolved metal reduction conditions and it was found that compounds possessing an N-benzyl substituent underwent preferential debenzylation and resisted further reduction. The complementary N-isobutyl functionalised materials only underwent the double reduction when a phenyl substituent was present.     

Unexpected products from the attempted organolithium-mediated conversion of β-methoxy aziridines into allylic amines

The organolithium-mediated conversion of cyclic trans-β-methoxy aziridines and cis-β-methoxy aziridines with a tertiary alkoxy group adjacent to the aziridine into the corresponding substituted allylic sulfonamides is reported. In all cases, unexpected products were observed and the reactivity was completely different from other related cis-β-methoxy aziridines. The product distributions are highly dependent on the organolithium reagent employed and the structure of the methoxy aziridine Thus, together with our previous reports, the full scope and limitations of this approach to allylic sulfonamides are established.     

Determination of Sulfonamides in Pharmaceuticals and Rabbit Plasma by Microchip Electrophoresis with LED-IF Detection

In this paper, we describe a compact and low-cost light-emitting diode-induced fluorescence (LED-IF) detection coupled to microchip electrophoresis for the determination of sulfonamides in pharmaceutical formulations and rabbit plasma. Three fluorescein isothiocyanate-labeled sulfonamides in rabbit plasma were separated in the running buffer of 40 mM phosphate buffer (pH 7.0) at the separation voltage of 2.0 kV, and detected by LED-IF detector in which the high-power blue LED was driven at the constant current of 150 mA and the emitted fluorescence over 510 nm was collected by a planar photodiode. The linear concentration ranged from 2.0 to 125.0 μg mL^?1, both for sulfadiazine and sulfamethazine with the correlation coefficients (r ²) of 0.995 and 0.997, respectively, and from 2.0 to 100.0 μg mL^?1 with the correlation coefficients (r ²) of 0.997 for sulfaguanidine. The limits of detection for the three sulfonamides were 0.36–0.50 μg mL^?1 (S/N = 3). Intra-day and inter-day precision of migration time and peak area for the determination of sulfonamides were <4.5 %. This method has been successfully applied to the analysis of sulfonamides in pharmaceuticals, and could be used to study the pharmacokinetics of sulfonamides in rabbit.     

On the α-lithiation-rearrangement of N-toluensulfonyl aziridines: mechanistic and synthetic aspects

A detailed study of the rearrangement of five cycloalkene N-toluenesulfonyl (tosyl) aziridines using sec-butyllithium (with and without added ligands such as (−)-sparteine and TMEDA) has been carried out. Allylic sulfonamides were the main products from the cyclopentene and cyclohexene aziridines whereas bicyclic sulfonamides were obtained from the cycloheptene and cyclooctene aziridines. In most cases, p-toluenesulfonamide (TsNH₂) was produced as a by-product and a mechanistic explanation for its formation is forwarded. These reactions are believed to involve α-lithiation to a lithiated aziridine which can then partition through two pathways: (i) rearrangement to allylic or bicyclic sulfonamides via C-H insertion reactions or (ii) reductive alkylation to alkenes via attack by sec-butyllithium and subsequent elimination of TsNH₂. In the (−)-sparteine reactions, the products were generated with 38-66% ee and the sense of asymmetric induction involved lithiation of the S-aziridine stereocentre. This is opposite to that observed with epoxides.     

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.     

Synthesis of functionally diverse bicyclic sulfonamides as constrained proline analogues and application to the design of potential thrombin inhibitors

Bicyclic sulfonamides were synthesized from 4-alkenyl N-alkenylsulfonyl l-prolines using a ring-closure metathesis reaction. Three types of bicyclic sulfonamides varying in the size of the second ring (5,5; 5,6; 5,7) were synthesized. A sulfonamide counterpart of an indolizidinone 2-carboxylic acid was synthesized and evaluated for its activity against the enzyme thrombin.     

Amino acids as selective sulfonamide acylating agents

Acylation of antimalarial and bacteriostatic sulfonamides with N-protected amino acids and peptides was carried out using standard peptide coupling methods. These acylation reactions are regioselective for the N⁴ nitrogen atom of diazine-containing sulfonamides. In contrast, only N¹ coupling was found for sulfisoxazole, an isoxazole-based sulfonamide. Computational studies suggest that a combination of geometrical, thermodynamic and electronic factors are responsible for the different reactivities reported.     

Operationally convenient method for preparation of sulfonamides containing α,α-difluoro-β-amino carbonyl moiety

We report here that the reactions of in situ generated unprotected α,α-difluoroenolates with various N-sulfonyl imines take place under operationally convenient conditions affording a novel type of fluorinated sulfonamides of high pharmaceutical potential. The reactions feature structural generality, excellent yields and can be easily scaled up for practical preparation of the target fluorine-containing sulfonamides.     

Ultraviolet spectrophotometric assay of p-aminobenzenesulfonamides

A simple ultraviolet spectrophotometric method for the assay of microgram amounts (0.1–25 μg/ml) of 16 different p-aminobenzenesulfonamides (sulfonamides) in 0.1 N sodium

hydroxide has been developed. The method is simple, accurate, and highly sensitive within the limits of the experimental conditions described and can be used in pharmacies for the assay of sulfonamides in tablets and in pharmaceutical industries for quality control or environmental monitoring as well. The present method is more rapid than any analytical assay reported for these compounds thus far. The values of λ_max and ?_max for these sulfonamides have also been presented.     

An efficient solventless method for the synthesis of N,N-dialkyl sulfonamide derivatives

Aza-Michael addition of sulfonamides to α,β-unsaturated esters efficiently proceeds in the presence of catalytic amount of sodium hydroxide (NaOH) and tetrabutylammonium bromide (TBAB) as a phase-transfer catalyst (PTC) under microwave irradiation to afford N,N-dialkyl sulfonamides as biologically interesting compounds in good to excellent yields and short reaction times.