REACTIONS OF N-(p-CHLOROSULFONYLPHENYL)MALEIMIDE

Abstract

N-Phenylmaltimide reacted with chlorosulfonic acid to give an excellent yield of the sulfonyl chloride (1), which with dimethylamine or aniline (2 equivs.) afforded the corresponding sulfonamides (2,3). However, use of more dimethylamine (4 equivs.) caused opening of the imido ring and addition to the double bond to yield the dimethylamide (12). Similar reaction with diethylamine in methanol resulted in nucleophilic ring-opening by the solvent leading to the methyl ester (13). Analogous reactions with morpholine, pyrrolidine and piperidine (3 equivs.) proceeded with addition and substitution to give 7–9. N-(p-chlorosulfonylphenyl)-3,4-dichloromaleimide (15) reacted with amines with substitution of both the 3- and sulfonyl chlorine atoms to give the sulfonamides (16–21).

3-Chloro-4-phenoxy-N-phenylmaleimide reacted with chlorosulfonic acid to give the bis-sultonyl chloride (22); condensation with dimethylamine caused displacement of the 4-(p-chlorosulfonyl-phenoxy) group to give 16. The various reactions are discussed and the structures of the products confirmed by microanalytical and spectroscopic data. The results of preliminary biological screening against 4 fungi and 2 enzymes are included.     

Rhodium(II)-catalyzed aziridination of allyl-substituted sulfonamides and carbamates

Several unsaturated sulfonamides underwent intramolecular aziridination when treated with PhI(OAc)(2), MgO, and catalytic Rh(2)(OAc)(4) to give bicyclic aziridines in excellent yield. Treatment of the resulting azabicyclic sulfonamides in methanol in the presence of p-TsOH resulted in exclusive opening of the aziridine ring at the most substituted position affording six- and seven-membered ring products in high yield. In contrast, the intramolecular aziridination of several cycloalkenyl-substituted carbamates did not require a Rh(II) catalyst and proceeded via an iminoiodinane intermediate. The resulting tricyclic aziridines underwent ring opening when treated with various nucleophiles to give anti-derived products as expected for nucleophilic attack at the three-membered ring. The iodine(III)-mediated reaction of a 3-indolyl-substituted carbamate, however, required a Rh(II) catalyst. The expected aziridine was not observed, but rather simultaneous spirocyclization of C(3) and stereoselective syn-acylation at C(2) occurred to give compound 41, whose structure was unequivocally established by an X-ray crystallographic study. The reaction proceeds in a stepwise manner via a metal-free zwitterionic intermediate which is attacked by a nucleophilic reagent on the same side of the amide anion. Related reactions occurred with both a 2-indolyl- and 3-benzofuranyl-substituted carbamate but with lower stereoselectivity.     

Solid Phase Extraction of Sulfonamides Using Cyclobond-I Cartridges

Abstract

The use of cyclobond-I solid phase extraction (SPE) cartridges in the analysis of sulfonamides was investigated. an aqueous solution of sulfonamides in 0.1 M potassium phosphate buffer (pH 4.0) was passed through the SPE cartridge. the sulfonamides which were retained on the cartridge by formation of inclusion complexes between the sulfonamides and B-cyclodextrin were eluted with 50% aqueous methanol. the eluate was directly analysed by High Performance Liquid Chromatograph with UV detection at 265nm.     

High Performance Liquid Chromatographic Determinations of Sulfonamides by Ionic Suppression

Abstract

A high pressure liquid chromatography procedure is reported for extraction and quantitation of 8 sulfonamides in stock solutions and in vitro plasma samples. This assay consists of a single, one-step extraction of sulfonamides from plasma and is sensitive to 10.0 ng/ml at 254 nm without additional concentration of the sample. Four sulfonamides (sulfamerazine, sulfamethazine, sulfapyridine and sulfathiazole) were separated from the plasma matrix by either mobile phase regardless of pH. The sulfonamides with the highest pKa, sulfanilamide (10.5) and sulfaguanidine (11.3), were only separable from plasma in a 50% water/50% methanol mobile phase at pH 7.45. The sulfonamide with the lowest pKa, sulfisoxazole (4.9), and its metabolite, acetylsulfisoxazole (N⁴), were separated from plasma by either mobile phase, 50/50 or 60/40 water/methanol, when acetate buffer reduced the pH to 4.00. Standard concentration curves of peak height were the most sensitive at 254 nm when a 60% water/40% methanol mobile phase at pH 4.00 was used. Sulfanilamide and sulfaguanidine were the most responsive to ultraviolet quantitation at 254 nm regardless of ionic suppression or polarity of the mobile phase.     

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.     

Practical preparation of N-(1-Alkynyl)sulfonamides and their remote diastereoselective addition to aldehydes via titanation

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. The acetylene-titanium complexes generated from N-(1-alkynyl)benzosultams underwent diastereoselective addition to aldehydes. [reaction: see text]     

High-performance liquid chromatography of sulfonamides and quinolones on p-tert-butyl-calix[6]arene-bonded silica gel stationary phase

The high-performance liquid chromatographic behavior of some sulfonamides and quinolones was studied on a p-tert-butyl-calix[6]arene-bonded silica gel stationary phase. The effect of mobile phase variables such as methanol content, ionic strength and pH on their chromatographic behavior was investigated. The retention behavior of sulfonamides on the stationary phase was compared with that on both Zorbax C₁₈-bonded silica gel and γ-(ethylenediamino)propyltriethoxylsilane-bonded silica gel (diamino-bonded phase). The retention mechanism of sulfonamides and quinolones on the stationary phase was also discussed. The results indicate that the stationary phase behaves as a reversed-phase packing and its separation selectivity is much better than that of not only Zorbax C₁₈ phase but also diamino-bonded phase. Some sulfonamides and quinolones were separated on the stationary phase, but the separation of sulfonamides is far more successful.     

Quantitative extraction of sulfonamides in meats by supercritical methanol‐modified carbon dioxide: A foray into real‐world sampling

Optimizing operational parameters and obtaining the highest possible recovery are two of the major objectives to be attained when any extraction process is performed on a real sample in which the true analyte concentration is unknown. Sulfadiazine (SDZ), sulfamerazine (SMR), and sulfamethazine (SMZ) were extracted from real samples of chicken liver, beef liver, and pig kidney, using methanol‐modified supercritical CO₂. The optimum extraction parameters were found to be 17.237 MPa and 160°C for two of the three analytes; SMZ, on the other hand, was completely extracted at 120°C. Under these conditions of high temperature, high amounts of modifier (3.0 mL of methanol in a 10‐mL extraction vessel) and low pressure, all three sulfonamides (SAs) were shown to be quantitatively extracted from spiked samples from domestic animals which had not been given sulfonamides. Under the same conditions, meat samples of commercial origin were analyzed. These results were compared with those obtained by conventional extraction methods. Almost all the meat samples contained sulfa drug residue levels far exceeding the current tolerance levels allowed for most sulfonamides. Eighteen of thirty samples contained at least one of the three sulfonamides, and seven of these samples contained from 1.1 to 4.2 mg kg^–1 of SMZ. The SAs were quantified by HPLC with UV absorbance and amperometric detection.     

An Efficient Method for Sulfonylation of Amines,Alcohols and Phenols with N-Fluorobenzenesulfonimide Under Mild Conditions

A new and convenient procedure was developed for the preparation of sulfonamides and sulfonic esters using N-fluorobenzenesulfonimide(NFSI) as a novel phenylsulfonyl group transfer reagent. In this protocol, a broad range of functional groups were tolerated to give the corresponding sulfonamides or sulfonic esters in moderate to excellent yields. The synthetic strategy for sulfonamides formation proceeded efficiently even under base-, metal-and additive-free conditions with the advantages of operational simplicity, mild reaction conditions as well as short reaction time.     

3-Oxo-1,2-benzoisothiazoline-2-acetic acid 1,1-dioxide derivatives. I. Reaction of esters with alkoxides

Reaction of 3-oxo-1,2-benzoisothiazoline-2-acetic acid alkyl esters 1,1-dioxide ( 1a-d ) with alkaline alkoxides was carried out under various conditions. Under mild conditions, o-(N-carboxymethylsulfamyl)benzoic acids dialkyl esters ( 2a-d ) were obtained with good yields. Reaction of 1a-d or 2a-d with sodium alkoxides under drastic conditions afforded 4-hydroxy-2H-1,2-benzothiazine-3-carboxylic acid alkyl esters 1,1-dioxide ( 3a-d ). Transesterification was observed when esters 1b-d were treated with sodium methoxide in methanol. Esters 3a-d were hydrolyzed in concentrated aqueous sodium hydroxide affording the acid 6 . Attempts to recrystallize 6 from water resulted in its decarboxylation to give 2H-1,2-benzothiazine-4-(3H)one 1,1-dioxide (7). Compound 6 could not be obtained by acid hydrolysis of esters 3a-d or by rearrangement of 3-oxo-1,2-benzoisothiazoline-2-acetic acid 1,1-dioxide ( 8 ). Different experimental evidence supports the suggestion that rearrangement took place by ethanolysis of the carboxamide linkage affording the open sulfonamides (fast step) followed by a Dieckmann cyclization (slow step). It was demonstrated that transesterification took place in the open sulfonamides 2 .     

Sulfur dioxide mediated one-pot, three- and four-component syntheses of polyfunctional sulfonamides and sulfonic esters: study of the stereoselectivity of the ene reaction of sulfur dioxide

The ene reaction of sulfur dioxide with enoxysilanes or with allylsilanes generates silyl sulfinates that can be brominated (Br(2) or NBS) or chlorinated (NCS or Cl(2)) to produce the corresponding sulfonyl halides. They react with primary and secondary amines or alcohols to give the corresponding sulfonamides and sulfonic esters, respectively. The hetero-Diels-Alder addition of sulfur dioxide to 1-oxy- or 1,3-dioxy-1,3-dienes generates zwitterions that add to enoxysilanes or allylsilanes giving silyl sulfinates that can be converted in situ into polyfunctional sulfonamides or sulfonic esters. This realizes quick access to libraries of complicated sulfonamides and sulfonic esters applying one-pot, three- and four-component methods.     

Pd(II)- and Pd(0)-cocatalyzed reactions of sulfonamides with MCPs

[reaction: see text] MCPs can efficiently react with sulfonamides in the presence of Pd(0) and Pd(II) catalysts to give the corresponding ring-opened products in high yields.     

Carbenium ion trapping using sulfonamides: an acid-catalysed synthesis of pyrrolidines by intramolecular hydroamination

Cyclisations of homoallylic sulfonamides proceed smoothly via carbenium ion generation using trifluoromethanesulfonic (triflic) acid, the ease of cyclisation being directly related to the ion stability to give good to excellent yields of the corresponding pyrrolidines. Both toluene- and nitrophenyl-sulfonyl groups are suitable for all substrates tested whereas the corresponding carbamates are only useful in cases of tertiary and highly stabilised carbenium ions. Polyene-derived sulfonamides can also be cyclised to the corresponding polycyclic systems in remarkably high yields, in reactions reminiscent of related cascades encountered in terpene biosynthesis.     

Tethered aminohydroxylation using acyclic homo-allylic sulfamate esters and sulfonamides as substrates

Homo-allylic sulfamate esters and sulfonamides are shown to be useful substrates for the tethered aminohydroxylation (TA) reaction. The sulfamate esters undergo the TA reaction delivering 1,2,3-oxathiazinane products whereas the sulfonamides give 1,2-thiazinane products. A range of acyclic homo-allylic sulfamate esters were prepared and subjected to the TA reaction to establish the scope of the process. Nucleophilic ring-opening reactions of the 1,2,3-oxathiazinane products are also described.     

流动注射在线预富集-高效液相色谱法测定水产品中4种磺胺类药物

建立了以活性碳纤维作吸附剂,流动注射在线预富集与高效液相色谱联用法测定水产品中4种磺胺类药物(磺胺噻唑、磺胺二甲嘧啶、磺胺间甲氧嘧啶、磺胺喹啉)残留含量的方法。样品经磷酸盐缓冲溶液提取后,采用活性碳纤维作吸附剂流动注射在线预富集,在pH 3.0的甲酸溶液-甲酸甲醇溶液(60∶40,V/V)的流动相体系中,用Eclipse XDB-C18色谱柱(250 mm×4.6 mm,5μm)分离,流速1.0 mL/min;检测波长270nm。结果表明,4种磺胺类药物在0.001～0.064 mg/L浓度范围内呈良好的线性关系,相关系数r为0.9997～0.9999;检出限为0.48～1.15μg/L(S/N=3);富集倍数在137～406之间;加标回收率为93.5%～104.0%。本方法操作简便、结果准确、灵敏度高。     

One-pot synthesis of sulfonamides from methyl sulfinates using ultrasound

Room temperature ultrasonic irradiation of neat mixtures of methyl sulfinates and primary or secondary amines (1.5 equiv) produced sulfinamides, which on m-CPBA oxidation (in dichloromethane) were converted into the corresponding sulfonamides. The two steps can be accomplished in one pot, in good overall yields, when using secondary amines, but primary amines give better sulfonamide yields when the peracid oxidation is effected on the purified sulfinamide. This constitutes a mild, efficient, and potentially scalable route to sulfonamides, which obviates the use of water sensitive, often lachrymatory sulfonyl chlorides and large reagent excesses.     

Determination of sulfonamide compounds in sewage and river by mixed hemimicelles solid-phase extraction prior to liquid chromatography-spectrophotometry

Mixed hemimicelles-based solid-phase extraction was investigated for the preconcentration of five sulfonamides from environmental water samples prior to HPLC-spectrophotometry determination in this paper. A comparative study on the use of sodium dodecyl sulfate (SDS) coating gamma-alumina or octadecyltrimethylammonium bromide (OTMABr) and OTMABr coating silica as sorbent materials were presented. The five analytes (sulfadiazine (SDA), sulfathiazole (STA), sulfapyridine (SPD), sulfamethazine (SMZ) and sulfamethoxazole (SMX)) were quantitatively adsorbed on OTMABr-gamma-alumina and OTMABr-silica mixed hemimicelles, but OTMABr-gamma-alumina was not adopted because it worked at a high pH (around 10), instead, OTMABr-silica was selected to overcoming the pH restriction. The analytes retained on the cartridge were quantitatively desorbed with suitable amounts of methanol. Factors influencing the extraction efficiency, such as the amount of surfactant, pH of sample and breakthrough volume were discussed. The proposed method had been applied to determining the five sulfonamides in several environmental water samples and concentration factors of 300 and 600 for SDA and other four analytes were achieved, respectively. Detection limits obtained ranged between 0.15 and 0.35microg/L for this five sulfonamides under the optimized conditions. The accuracy of the method was evaluated by recovery measurements on spiked samples, and good recovery results (89-113%) with precision of 3-6% were achieved.     

Clivage réducteur des sulfonamides et des sulfonates par les métaux alcalins dissous dans le hmpt

Alkali metal solutions in hexamethylphosphotriamide effect the cleavage of various sulfonamides and sulfonates under mild conditions.Sulfonamides give amines in good yields: the presence of a protic cosolvent is not necessary. Sulfonates of all types (e.g. tosylate, benzylate, mesylate) give the alcohol always contaminated with a little of the corresponding hydrocarbon.     

Catalyzed hydroboration of allyl sulfonamides

The hydroboration of allyl sulfonamides (4-H₃CC₆H₄SO₂NRCH₂CH=CH₂: R=H, 1; Ph, 2; Bz, 3) with catecholborane (HBcat) using different rhodium catalysts has been examined using multinuclear NMR spectroscopy. Reactions give complex product distributions, regardless of the choice of catalyst, arising from a competing isomerization reaction. This isomerization reaction can be used with N-substituted allyl sulfonamides 2 and 3 to give the corresponding enamines (4-H₃CC₆H₄SO₂CH=CH₂CH₃), which in turn react with HBcat to give regioselective formation of one isomer (4-H₃CC₆H₄SO₂NRCH₂CH₂(Bcat)CH₃).     

Ring opening of 2-(bromomethyl)-1-sulfonylaziridines towards 1,3-heteroatom substituted 2-aminopropane derivatives

1,3-Heteroatom substituted 2-aminopropane derivatives have been prepared from 2-(bromomethyl)-1-sulfonylaziridines for the first time using sodium azide or different potassium phenoxides in water in the presence of silica gel. The applicability of 1-arenesulfonyl-2-(bromomethyl)aziridines for the synthesis of functionalized sulfonamides has also been demonstrated towards different 1,3-dialkoxy-2-(tosylamino)propanes and 1,3-dialkylthio-2-(tosylamino)propanes upon treatment with the appropriate sodium alkoxide or sodium alkylthiolate in the corresponding alcohol or in methanol, respectively.