Sulfonamide nucleophiles, deprotonation

Acylation of a usually non-nucleophilic cyclic sulfonamide 52 has also been achieved under by deprotonation of the N-H by butyllithium followed by addition of various unsaturated acid chlorides (Equation 10) <2005TA761>. 

Sulfonamides of primary amines are readily deprotonated (pAia 9-11) and can thus be N-alkylated or N-arylated. Because of their high nucleophilicity and low basicity, deprotonated sulfonamides also react smoothly with less reactive electrophiles, such as n-alkyl bromides [136] (Table 8.9). Sulfonamides can also be N-alkylated with aliphatic alcohols under Mitsunobu conditions. Suitable solvents for the N-alkylation of sulfonamides on polystyrene by Mitsunobu reaction are DCM, toluene, and THF. 

The reaction of arenesulfonyl chlorides with alcohols to yield sulfonates is relatively slow (if compared, e.g., with the formation of mesylates or sulfonamides), and treatment of diols with tosyl chloride can readily yield the statistically expected amount of monotosylated product [35, 36]. The selectivity of such reactions can sometimes be enhanced by additives such as AgO [37] or Bu2SnO [38]. Deprotonation of the diol can be used to increase its nucleophilicity and thereby reduce the reaction time (Scheme 10.9). This strategy can, however, lead to problems, because the products are sensitive toward strong bases, and may cyclize, oligomerize, or undergo elimination. 

Camphor-10-sulfonic acid (1) is available in large quantities in both enantiomeric forms. In only 3 steps the cyclic sulfonamide 2 (sultam) can be synthesized, which can be acylated with acid chlorides after deprotonation with sodium hydride (Scheme 1) [1, 2]. The resulting amides 3 are considerable more reactive towards nucleophiles than the corresponding carboxylic esters and the a,/ -unsaturated derivatives undergo, with excellent selectivities, Diels-Alder reactions or Michael additions under mild conditions. Al-... 

Ring formations by nucleophilic substitution at saturated carbon atoms with primary amines as nucleophiles have rarely been carried out because the resulting secondary amines as a rule are more nucleophilic than the primary ones, and therefore competition reactions are favored. The synthesis of secondary amines often starts from toluene sulfonamides which can easily be deprotonated and alkylated. A large number of methods for detosylation exists especially the acidic cleavage with H2SO4 or with HBr/phenol have proved to be reliable. 

Polymerization of racemic aziridines afforded soluble polymers, whereas the use of enantiopure aziridines provided sparingly soluble polymers. KHMDS serves to deprotonate the primary sulfonamide initiator, providing an amide anion, which then functions as a nucleophile to promote the ring-opening polymerization of the aziridine. The polymerization kinetics were shown to feature a first-order dependence on both the aziridine substrate and the anionic initiator. 

---