Pyridines, acylation sulfonation

Pyridine lies near one extreme in being far less reactive than benzene toward substitution by electrophilic reagents. In this respect it resembles strongly deactivated aromatic compounds such as nitrobenzene. It is incapable of being acylated or alkylated under Friedel-Crafts conditions, but can be sulfonated at high temperature. Electrophilic substitution in pyridine, when it does occur, takes place at C-3. 

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. 

Sulfonic esters are most frequently prepared by treatment of the corresponding halides with alcohols in the presence of a base. The method is much used for the conversion of alcohols to tosylates, brosylates, and similar sulfonic esters. Both R and R may be alkyl or aryl. The base is often pyridine, which functions as a nucleophilic catalyst, as in the similar alcoholysis of carboxylic acyl halides (10-21). Primary alcohols react the most rapidly, and it is often possible to sulfonate selectively a primary OH group in a molecule that also contains secondary or tertiary OH groups. The reaction with sulfonamides has been much less frequently used and is limited to N,N-disubstituted sulfonamides that is, R" may not be hydrogen. However, within these limits it is a useful reaction. The nucleophile in this case is actually R 0 . However, R" may be hydrogen (as well as alkyl) if the nucleophile is a phenol, so that the product is RS020Ar. Acidic catalysts are used in this case. Sulfonic acids have been converted directly to sulfonates by treatment with triethyl or trimethyl orthoformate HC(OR)3, without catalyst or solvent and with a trialkyl phosphite P(OR)3. ... 

The third procedure illustrated by this preparation involves the reaotion of ketones with trifluoromethanesulfonic anhydride in a solvent such as pentane, methylene chloride, or carbon tetrachloride and in the presence of a base such as pyridine, lutidine, or anhydrous sodium carbonate.7-11,15 This procedure, which presumably involves either acid-catalyzed or base-catalyzed enolization of the ketone followed by acylation of the enol with the acid anhydride, has also been used to prepare other vinyl sulfonate esters such as tosylates12 or methanesulfonates.13... 

An additional means of performing a selective cross-benzoin was reported in 2001 when Mnrry and co-workers expanded benzoin methodology to include trapping of acyl imines XIX formed in situ (Scheme 6) [53], The authors chose to use a-amido sulfones due to their stability and the relative ease of acyl imine liberation. The parent reaction combines pyridine 4-carboxaldehyde 51 and tosylamide 52 in 98% yield in the presence of pre-catalyst 54 and triethylamine (Scheme 6). 

Selective o/t/io-acylation and orrfio-formylation of 2-alkyl pyridines is possible by [2,3] sigmatropic rearrangement (Sommelet-Hauser) of a-pyrrolidinyl-2-alkylpyridine sulfonates (268), prepared by treating the parent base with cyanomethyl benzenesulfonate (76JOC2658). Acid hydrolysis of the rearranged product (269 R = H) yields 3-formyl-2-methylpyridine (270). Methylation of (269 R = H) using NaH-Mel and acid hydrolysis of the reaction mixture gives 3-acetyl-2-methylpyridine (270 R = Me). 

Uncommon IPRs were tested recently. Polymerized acyl monoglydnate surfactant was found to be as effective as sodium dodecylsulfate for the resolution of organic amines [126]. For the analysis of pyridine-based vitamins in infant formnlas, dioc-tylsulfosuccinate produced a unique retention pattern [133], Among bizarre IPRs, tris(hydroxymethyl)aminomethane was used for the determination of cyclamate in foods. It was selected over different ion-pair reagents such as triethylamine and dibu-tylamine, based on sensitivity and time economies [134]. Hexamethonium bromide, a divalent IPR, was used successfully to separate sulfonates and carboxylates [135]. 

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