5- Bridged sulfonamides

Disubstituted 3-bridged Sulfonamides. The 4-bromo-3-rm-butylsulfonamide 26 described earlier provided a useful intermediate for the current syntiieses. For example, 26 could be treated with 2 eq LDA (here BuLi induces transmetalation as... 

Bridged Sulfonamides. The most convenient syntheses of 3-bridged pyrazole sulfonamides utilizes either a mercapto group or amine functionality as a handle to prepare the requisite sulfonamide. For example, one can prepare a pyrazole sulfonamide with many of the required substituents by the scheme depicted below. Condensation of methyl hydrazine with chloroacrylonitrile yields N-methyl-3-aminopyrazole 58 (12-13). The amine is protected by acylation. Chlorination at the 4 position with sulfuryl chloride, followed by deprotection provides 3-amino-4-chloropyrazole 59. The sulfonamide 60 is prepared by decomposition of the diazonium salt of 59 in SO2/CUCI followed by amination of the resulting sulfonyl chloride. 

Substituted-2-bridged Sulfonamides. This isomer is the easiest to synthesize due to the propensity of 3-substituted thiophenes to undergo electrophilic substitutions or directed metalations in the 2 position. Thus, the "Harmony" reverse isomer can be prepared from acid 32 via a directed metalation to the 2 position. The usual SO2... 

Disubstituted-4-bridged Sulfonamides. All of the 2,3-disubstituted isomers that we ve prepared were made from the acid-thioether 23. In this case the acid is used to direct metalation to the 2 position, and is quenched with a variety of electrophiles yielding 43. The acid is then esterified prior to oxidative chlorination/amination. 

Bridged Sulfonamides. For the 4-bridged pyrazole sulfonamides, the sulfonamide group is almost exclusively introduced by a chlorosulfonation/amination scheme. Any functionality which can tolerate the chlorosulfonation reaction conditions may be present initially, or may be introduced in a subsequent step if necessary. 

In the synthesis of commercial sulfur-heterocycles two interesting reactions are used (i) diphenylamines may be connected by a sulfur bridge in the orfho-positions (ii) the amino grouping of sulfonamides undergoes condensation reactions with neighboring imino- and amide groups. 

Fig. 5.5 Putative interactions of the cocrystallized selective Cox2 ligand SC-558 with its active site, assuming a neutral sulfonamide group - the state used to assign pharmacophore feature flags by the used software. Dotted lines stand for hydrogen bonds, the other residues being responsible for hydrophobic contacts. From a physicochemical point of view, an ionized SO2 NH involved in a salt bridge with Arg 513 and hydrogen bonding to the other tautomer of His 90 would make more sense.

When macrocycle 65 is synthesized, the in/out isomer of [2]catenane 79 is also formed in 11% yield (Figure 29) [46]. A first attempt to methylate both sulfonamide groups by treatment of the DMF solution of 79 with iodomethane and potassium carbonate was successful. By bridging the two sulfonamide units with a bifunctional alkylating reagent, we were able to synthesize the first pretzel-shaped molecule [54]. Considerations of the X-ray structure analysis of amide-linked catenanes [16] and CPK models led to the diiodo compound 95 as a suitable brid-... 

Figure 37. Synthesis of the first pretzelane 96 by intramolecular bridging of the two sulfonamide groups bearing macrocycles of [2]catenane 79.

Sulfonamide groups incorporated in rotaxanes enable the construction of new topological assemblies provided with mechanically and covalently bonded subunits. Methylation of a [2]rotaxane containing a sulfonamide unit in the axle revealed that the substitution reaction is not sterically hindered by the macrocycle. Similar to the synthesis of the pretzelane 96, the two sulfonamide groups of rotaxane 80m were bridged with 95 to form 100 in 71% yield (Figure 39) [46]. The additional covalent bond converts the former [2]rotaxane into a [l]rotaxane and reduces the mobility of the wheel along the axle. Rotaxanes 80m and 100 are his-... 

The bridging of sulfonamide groups with diiodo compounds can also be applied to the intermolecular coupling of rotaxanes. When rotaxane 80e was treated with 95 under standard conditions, 76% of the wheel-bis[2]rotaxane 102 and 8% of the iodine-substituted rotaxane 101 were isolated (Figure 40) [46]. 101 is an excellent substrate for the synthesis of higher and unsymmetric rotaxane assemblies. 

So far the rotaxanes were bridged via the macrocycles, but coupling can also occur at sulfonamide-bearing axles. Reaction of 57m with 95 results in 48% of the axle-bis[2]rotaxane 107, which can be considered as a [3]rotaxane (Figure 43) [42]. The translational freedom of the wheel along the thread is strongly impeded not only by the second wheel, but also by the attached podand-like chain. 

The pretzel-shaped molecule 96 (the first pretzelane ) was synthesized by intramolecular bridging of the two sulfonamide units of 79 with a bifunctionalized podand-like chain [54]. Again the enantioseparation of 96 was accomplished with a baseline quality separation and a large separation factor (a=5.20). Preparative separation of the enantiomers enabled the detection of the circular dichrogram of 96 (Figure 48). The optical rotation values of 79 and 96 were both determined to be [aD] = 168° (Troger base [aD] = 281°). 

The water-soluble reactive phthalocyanine dyes (see Section 2.8) yield brilliant turquoise and green shades not available from any other dye category. The most important reactive phthalocyanine dyes contain copper or nickel as their central atom they are substituted with sulfonic acid groups and also with reactive groups joined via sulfonamide bridges. An example is C.I. Reactive Blue 15, 74459 [12225-39-7] (23) ... 

Mechanically connected components of sulfonamide catenanes and rotaxanes can also be connected in an intramolecular manner by linking their sulfonamide moieties and producing the first pretzel-shaped compound 17 [48] and [ljrotaxane 18 [49], respectively. Interestingly, the [l]rotaxane can be bridged intramolecularly giving rise to a molecular 8 compound 19 [50],... 

In 1996 we reported on the first covalent dimerization of the [2]rotaxane with sulfonamide function in its wheel component to give a [3]rotaxane 32 (bis[2]rotaxane) [49], Subsequently, we expanded the concept of covalent bridging and produced more elaborate rotaxane assemblies such as an unsymmetrical bis[2]rotaxane 33, and 34,... 

Plants. Degraded rapidly. DT50 1.5-4.5 days main metabolic pathways were hydrolysis of the sulfonyl urea bridge to form the pyridine sulfonamide and pyrimidine amine, and hydroxylation on the pyrimidine ring... 

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