Sulfonamides directed lithiation

We might expect that the sulfonamide group in 155 would direct lithiation of the thiophene ring to its adjacent site in an ortho -lithiation. It doesn t. An a-lithiation to give 156 occurs instead... 

Secondary and tertiary sulfonamides are among the most powerful ortho-directing groups known. There is no danger of attack at S, and N,N-dimethylsulfonamides 249 may be lithiated with n-BuLi alone.218 Secondary N-f-butyl sulfonamides 250 are particularly useful because the f-butyl group is readily removed in polyphosphoric acid. Carbonation of 251 and cyclisation in acid gives the saccharin analogues 252.133... 

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. 

The preparation of the saccharin derivative 305 (Scheme 74), substituted with thiomethyl group at C-5 and directly functionahsed at nitrogen with a chain containing the bromo atom at C-4, was prepared according to Method N. The substituted sulfonamide 304 was prepared by reaction of 303 in sequence with CISO3H, 4-aminobutanol and 2,3-dihydropyran. 304 was ortho-lithiated and carbonylated and the corresponding intermediate was finally cyclised, deprotected at the oxygen atom and transformed into the AT-bromobutylsaccharin 305 [100]. 

The secondary sulfonamido group (—SO2NHR) appears to have a partial orrAo-directing effect on lithiation. Thus treatment of A-ferf-butylthiophene-2-sulfonamide (117) with n-BuLi gives a mixture of the two dianions (118) and (119) (Equation (11)), Under kinetically controlled conditions, the ratio (118) (119) is 2.7 1, but on equilibration, (119) precipitates out from the mixture, thereby driving the equilibrium towards the 5-lithio isomer <9iJOC4260>. The directing effect of the anionic sulfonamide does not appear to be as pronounced as that of the anionic carboxamide. 

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