Directing substituents, sulfonamides

Sulfonamides as ortho-directing substituents for metalating aromatic systems opened the door to synthetic routes to cyclic sulfonic esters (sultones) and amides (sultams). The first step in this procedure for preparing sultams involved the 2-metalation of N-alkylbenzenesulfonam-ides (52) and condensation with a variety of ketones. The tertiary alco-... 

The selective reaction of anionic 3,6-dichloro-4-sulfanilamidopy-ridazine with excess methanolic methoxide at the 3-position is another indication of the absence of major steric effects in most nucleophilic substitutions, as a result of the direction of nucleophilic attack (cf. Section II, A, 1). The selectivity at the 3-position is an example of the interaction of substituent effects. The sulfonamide anion deactivates both the 3-chloro (ortho direct deactivation) and... 

The first synthesis of optically pure N-methylated derivatives of Ala, Leu, Phe, and Tyr was published by Fischer and Lipschitz in 1915 73 using the sulfonamide method. Two main developments have ensured that this method remains useful for the preparation of TV-alkyl amino acids both in solution and solid phase (1) the introduction of the Mitsunobu reaction for the alkylation step and (2) the introduction of replacements for Tos (such as the Fukuyama Nbs) that allow easy removal of the sulfonamide protecting group after the alkylation step. Sulfonamide-protected amino acid derivatives can be alkylated in two different ways. Because of the acidity of the sulfonamide hydrogen it is possible to introduce the N-substituent either by direct alkylation (e.g., alkyl halides) or by the Mitsunobu reaction 74 (Scheme 4). 

More powerful directing groups such as those based on amides and sulfonamides are successful with pyridines as with carboxylic rings, and will not be discussed separately. The enhanced acidity of pyridine ring protons makes the simple carboxylate substituent an ideal director of lithiation in pyridine systems.257 The pyridinecarboxylic acids 367-369 are deprotonated with BuLi and then lithiated with an excess of LiTMP all the substitution patterns are lithiated nicotinic acid 368 is lithiated in the 2-position. The method provides a valuable way of introducing substituents into the picolinic, nicotinic and isonicotinic acid series. 

Methylthiophene is metallated at the S-position whereas 3-methoxy-, 3-methylthio-, 3-carboxy-, and 3-bromo-thiophenes are metallated at the 2-position. 2-Substituents which have been used to direct metallation to C(3) of thiophene include oxazoline, imidazoline, secondary carboxamide, carboxylate, sulfonamide, and -aminoalkoxide. For... 

For the rate of acetylation of six sulfonamide drugs in the rat (6) the highest correlation was obtained in Equation 22. If we neglect the second term on the left of the equation and analyze the log kAc values directly with the substituent parameters, the correlation becomes poorer as shown in Equation 25. For data obtained independently on 10 drugs (7), Equation 28 shows the best correlation. An F test shows that the ApKa term in Equation 29 is justified only at the 0.75 level of significance. For 10 drugs used with rabbit (7) and human (8), Equations 31 and 34 show the best correlation. 

Unsaturated Hydrocarbon-Substituted Sulfonamides. N-substituents containing double bonds gave either fast or delayed action at 1% concentration (Table 3). Double bonds directly attached to the nitrogen (phenyl (X) and vinyl (VII)) gave fast kill at 1%, whereas the methylene interrupted allyl (VIII), and benzyl (XI) substituents gave excellent delayed activity. Hie allyl (VIII) analog had Class IV activity. 

Several different substituents located at position 2 of thiophene have shown the ability, fully or partially, to direct metalation to position 3 oxazoline, imidazoline, secondary carboxamide, carboxylate, sulfonamide and a-aminoalkoxide. The ultimate objective is to secure a high-yielding, regioselective route for the synthesis of 2,3-disubstituted thiophenes. 

The method of choice selected for the coupling process will depend on one of several factors. The original coupling route via the addition of the sulfonylisocyanate to the heterocyclic amine has been used for both laboratory and manufacturing scale preparations. This route provides excellent yields of high purity sulfonylurea with a minimum of by-products. It is the most direct route from basic raw materials. However, it can not be used when a substituent on the sulfonamide is sensitive to HCl or when another product, such as a cyclic dimer of the sulfonylisocyanate, is the major phosgenation product. 

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