Pyridine—Sulfur Trioxide

The use of sulfur trioxide as a sulfonating agent is often inconvenient, and reactions carried out with it are usually vigorous and difficult to control. The addition compounds-that sulfur trioxide forms with tertiary amines and other strong electron donors, however, have been found to be very convenient sulfonating agents. Procedures for the preparation of three typical compounds, pyridine-sulfur trioxide, CsHsN-SOa dimethylaniline-sulfur trioxide, CeHs-N(CH3)2 SOs and dioxane-sulfur trioxide, 0(CH2 CH2)20 -SO3, are presented here. 

A solution of 62 g. of dry pyridine in 350 ml. of dry chloroform is placed in a three-necked flask fitted with a thermometer, mechanical stirrer, and a dropping funnel. The flask is cooled by an ice-salt mixture while 38.5 g. of chlorosulfonic acid is slowly added to the solution, with continuous stirring. The rate of addition is regulated so that the temperature of the reaction mixture is kept in the neighborhood of 0°. At the end of the reaction, the solid pyridine-sulfur trioxide (pyridiniuin chloride remains in solution) is filtered on a Buchner funnel and quickly washed four times with 30- to 40-ml. portions of ice-cold chloroform. The product is then placed between porous 

This compound is prepared in the same way as the pyridine compound. Suitable proportions are 45 g. of purified dimethylaniline in 80 ml. of chloroform and 19.5 g. of chlorosuKonic acid. Yield 16 g. (48 per cent). 

Caution. Since pure dioxane-sidfur trioxide sometimes decomposes violently on standing for some time at room temperature, it should be prepared immediately prior to use.  

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Both pyrrole and furan can be sulfonated in the 2-position by treatment with the pyridine-sulfur trioxide complex (Scheme 14). Furan can be further sulfonated by this reagent to give the 2,5-disulfonate. 

Sulfonation with sulfur trioxide, pyridine sulfur trioxide, pyridine bis-sulfur trioxide, and dioxane sulfur trioxide, which are useful sul-fonating agents for acidophobic substances, have been applied to the thiophene seriesd At room temperature the 2-monosulfonic acid (isolated as the barium salt) is obtained in 86% yield. Higher temperatures lead to a disulfonic acid. However, sulfonation with chloro-sulfonic acid appears to be more convenient,as the sulfonyl chloride obtained can be used directly for the preparation of derivatives. 

The sulfonating actions of pyridine-sulfur trioxide, pyridine-bis sulfur trioxide and dioxane sulfur trioxide on 2,5-dimethyIthiophene have been compared. Yields of 95% monosulfonic acid were obtained with the latter two reagents, whereas pyridine sulfur trioxide yielded only 75%. 2-Methyl-3,5-diphenylthiophene resists formylation and SnCl4 Catalyzed acylation in contrast to 2,3,5-trimethylthiophene, which is formylated and acylated quite easily. 

To a stirred solution of 4.6 g (0.01 mol) of anhydrous oxytetracycline in 40 ml of dry tetrahydrofuran is added 3.5 g (0.021 mol) of pyridine-sulfur trioxide complex. After 16 hours of stirring at room temperature, the resulting suspension is filtered, and the solid is slurried with 25 ml of 2% hydrochloric acid for 10 minutes, filtered and thoroughly washed with methanol followed by ether. The pale yellow crystalline 5-oxytetracycline-6, 12-hemiketal-12-sulfuric acid ester melts at 210°C. 

Iodine, Pyridine, Sulfur trioxide Anon., J. Chem. Educ., 1973, 50, A293... 

Formamide, Pyridine, Sulfur trioxide See Formamide Iodine, etc. 

Ethyl sulfate Flammable liquids Fluorine Formamide Freon 113 Glycerol Oxidizing materials, water Ammonium nitrate, chromic acid, the halogens, hydrogen peroxide, nitric acid Isolate from everything only lead and nickel resist prolonged attack Iodine, pyridine, sulfur trioxide Aluminum, barium, lithium, samarium, NaK alloy, titanium Acetic anhydride, hypochlorites, chromium(VI) oxide, perchlorates, alkali peroxides, sodium hydride... 

Replacement of an allylic hydroxyl without saturation or a shift of the double bond was achieved by treatment of some allylic-type alcohols with triphenyliodophosphorane (PhjPHI), triphenyldiiodophosphorane (PhsPIj) or their mixture with triphenyl phosphine (yields 24-60%) [612]. Still another way is the treatment of an allylic alcohol with a pyridine-sulfur trioxide complex followed by reduction of the intermediate with lithium aluminum hydride in tetrahydrofuran (yields 6-98%) [67 J]. In this method saturation of the double bond has taken place in some instances [675]. 

The first studies on the sulfation of organic compounds, amino acids, and proteins have shown that pyridine/sulfur trioxide complex (pyridine/S03 or pyridine/Cl S03H),168-721 concentrated sulfuric acid,173,74 sulfuric acid//V,A -dicyclohexylcarbodiimide,175,761 and chloro-sulfonic acid177 are the most efficient reagents for the sulfation of tyrosine. More recently, alternative methods based on dimethylformamide/sulfur trioxide complex (DMF/S03),152,781 trimethylamine/sulfur trioxide (Me3N/S03),1152,1531 pyridinium acetylsulfate,137,791 and pyr-idinium trifluoroacetylsulfate1801 have been proposed to minimize side reactions which are difficult to control for the chemical sulfation of tyrosine peptides. 

Sulfation with Pyridine/Sulfur Trioxide Complex... 

Scheme 4 Sulfation of the N -Protected CCK-Heptapeptide with Pyridine/Sulfur Trioxide Complex1881 Ac—Tyr—Met—Gly—Trp—Met—Asp—Phe—NH2 5...

Figure 6 Rates of Sulfation of the Hirudin-Peptides with Pyridine/Sulfur Trioxide and of Epimerization of the C-Terminal Asu Residue1931"...

Scheme 12 Postsynthetic Protection of Unsulfated Human CCK-33 at Amino and Hydroxy Groups prior to Sulfation with Pyridine/Sulfur Trioxide Complex Followed by Suitable Deprotection Steps 551...

One of the first compounds to be introduced to the clinic, aztreonam (40-9), has been produced by total synthesis. Constmction of the chiral azetidone starts with amide formation of L-threonine (40-1) via its acid chloride treatment with ammonia leads to the corresponding amide (40-2). The primary amino group in that product is then protected as its carbobenzyloxy derivative (40-3). Reaction of that product with methanesulfonyl chloride affords the mesylate (40-4). Treatment of that intermediate with the pyridine sulfur trioxide complex leads to the formation of the A -sulfonated amide (40-5). Potassium bicarbonate is sufficiently basic to ionize the very acidic proton on the amide the resulting anion then displaces the adjacent mesylate to form the desired azetidone the product is isolated as its tetrabutyl ammonium salt (40-6). Catalytic hydrogenation over palladium removes the carbobenzyloxy protecting group to afford the free primary amine (40-7). The... 

Pyridine-sulfur trioxide Pyridine, compound with sulfur trioxide... 

With a Grignard reagent, 1-methylquinolinium ions give products of type (284). A notable reaction of this class is that between the pyridine-sulfur trioxide complex and sodium cyclopentadienide (286)... 

Pyridine iV-sulfides are known only in the form of their derivatives. Thus, 1-arylthiopyridinium cations (from pyridine and sulfenyl chloride) react with KCN to form ArSCN and pyridine (81CC703). Pyridine-sulfur trioxide is a mild sulfonating reagent, used for sulfonation of furan and pyrrole. 

The range of preparatively useful electrophilic substitution reactions is often limited by the acid sensitivity of the substrates. Whereas thiophene can be successfully sulfonated in 95% sulfuric acid at room temperature, such strongly acidic conditions cannot be used for the sulfonation of furan or pyrrole. Attempts to nitrate thiophene, furan or pyrrole under conditions used to nitrate benzene and its derivatives invariably result in failure. In the case of sulfonation and nitration milder reagents can be employed, i.e. the pyridine-sulfur trioxide complex and acetyl nitrate, respectively. Attempts to carry out the Friedel-Crafts alkylation of furan are often unsuccessful because the catalysts required cause polymerization. 

Thiophene is very easily sulfonated 95% H2SO4 at 30-40 °C converts it to the 2-sulfonic acid in a few minutes. Thiophene-2-sulfonyl chloride can be easily prepared by the action of chlorosulfonic acid on thiophene. Mono- and di-sulfonic acids of thiophene have been prepared by sulfonating thiophene with S03 or pyridine-sulfur trioxide (63AHCd)t). Sulfon-ation of 2-methyl-3,5-di-t-butylthiophene gives 2-methyl-5-t-butylthiophene-3-sulfonic acid (63AHC(l)l). However, 2,5-di-r-butylthiophene is monosulfonated normally at the 3-position (63AHC(l)l) under forcing conditions 2-(-butylthiophene-3,5-disulfonic acid is obtained. 

In view of the development of the synthesis of various aromatic and heterocyclic compounds from pyrylium salts (80T679), the preparation of the unsubstituted pyrylium salt from pyridine is noteworthy (Scheme 269) (53CB1327). The pyridine-sulfur trioxide complex undergoes ring opening to the sodium salt of pent-2-ene-1,5-dial. This salt cyclizes in perchloric acid via the red oxonium salt. 

There are several methods reported in the literature for transforming vicinal diols into ct-diketones while avoiding the risk of C-C bond cleavage.26 Examples include the standard Swem conditions (dimethyl sulfoxide and oxalyl chloride followed by triethylamine), or the use of DMSO activated by acetic anhydride, pyridine-sulfur trioxide complex, or dicyclohexylcarbodiimide (Mq/J-att oxidation). Diones are also obtained by treatment with benzalacetone as a hydride acceptor in the presence of catalytic amounts of tris(triphenylphosphine)ruthenium dichlonde [(PPh RuCFl.27 Recent developments include the use of w-iodoxyben/.oic acid28 or the oxoammonium salt of 4-acctamidoletramethylpipcridine-1-oxyl and y -toluencNulfonic acid.29... 

O-Sulfation of 138 by pyridine-sulfur trioxide occurs exclusively at 0-2,342 whereas phosphorylation affords several products.343,344... 

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