Dimerization reactions sulfonamides

The ruthenium carbene catalysts 1 developed by Grubbs are distinguished by an exceptional tolerance towards polar functional groups [3]. Although generalizations are difficult and further experimental data are necessary in order to obtain a fully comprehensive picture, some trends may be deduced from the literature reports. Thus, many examples indicate that ethers, silyl ethers, acetals, esters, amides, carbamates, sulfonamides, silanes and various heterocyclic entities do not disturb. Moreover, ketones and even aldehyde functions are compatible, in contrast to reactions catalyzed by the molybdenum alkylidene complex 24 which is known to react with these groups under certain conditions [26]. Even unprotected alcohols and free carboxylic acids seem to be tolerated by 1. It should also be emphasized that the sensitivity of 1 toward the substitution pattern of alkenes outlined above usually leaves pre-existing di-, tri- and tetrasubstituted double bonds in the substrates unaffected. A nice example that illustrates many of these features is the clean dimerization of FK-506 45 to compound 46 reported by Schreiber et al. (Scheme 12) [27]. 

An alternative sequence to avoid dimer formation in the synthesis of bosentan has appeared in the patent literature. The SNAr reaction with ethylene glycol is carried out first and the primary alcohol protected as the acetate ester 30. The second displacement with sulfonamide 24 and saponification of the ester protecting group then provide bosentan (l).29 This route is reported to provide the product in high purity and yield, but lacks the advantages of improved throughput afforded by the optimized route. 

Dicy do hexyl carbodiimide (DCC) should not be used as the insoluble dicyclohexyl urea (DCU) by-product is very difficult to remove, leaving residual DCU that can contaminate future reactions. Also, no dimerization of the HOBT ester of 3-carboxypropane sulfonamide 6 occurs as the sulfonamide is nonreactive toward HOBT esters. This was also observed by Ellman (38). 

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