Heterocyclic sulfonamides, synthesis

Once it was realized that heteroaromatic sulfonamides could be prepared and converted to sulfonylureas, and that these compounds possessed many of the desirable hebicidal qualities of the benzene sulfonylureas, a large synthetic effort was started to prepare more examples. Using thiophene and pyrazole as representative examples, we have been able to synthesize all of the positional isomers of the mono- and di-substituted sulfonamides. This paper will outline the major synthetic pathways that we have discovered, emphasizing directed metallation processes and nucleophilic substitution reactions, leading to the preparation of these heterocyclic sulfonamides. Many of tiie methods developed for thiophene and pyrazole sulfonamide synthesis have been extended to the synthesis of pyridine and other heteroaromatic sulfonamides. 

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. 

Tanaka and Ohno developed the palladium(0)-catalyzed cyclization of bromoallene 222 bearing a sulfonamide for the synthesis of medium-sized heterocycle 223 (Scheme 37).48b In this reaction, bromoallene acts as an allyl dication equivalent 224, and two different nucleophiles can be introduced regioselectively. The intramolecular nucleophilic... 

This procedure is satisfactory for the synthesis of a variety of aryl sulfonamides. The heterocyclic intermediate used in the synthesis of chlorsulfuron is prepared according to K. R. Hoffmann and F. C. Schaeffer (Ref. 5) as shown in Figure 5. 

Oxidative amination of carbamates, sulfamates, and sulfonamides has broad utility for the preparation of value-added heterocyclic structures. Both dimeric rhodium complexes and ruthenium porphyrins are effective catalysts for saturated C-H bond functionalization, affording products in high yields and with excellent chemo-, regio-, and diastereocontrol. Initial efforts to develop these methods into practical asymmetric processes give promise that such achievements will someday be realized. Alkene aziridina-tion using sulfamates and sulfonamides has witnessed dramatic improvement with the advent of protocols that obviate use of capricious iminoiodinanes. Complexes of rhodium, ruthenium, and copper all enjoy application in this context and will continue to evolve as both achiral and chiral catalysts for aziridine synthesis. The invention of new methods for the selective and efficient intermolecular amination of saturated C-H bonds still stands, however, as one of the great challenges. 

Torok and co-workers312 have reported the one-pot synthesis of /V-arylsulfonyl heterocycles through the reaction of primary aromatic sulfonamides with 2,5-dimethoxytetrahydrofuran. When triflic acid is used in catalytic amount, IV-arylsulfonylpyrroles are formed (Scheme 5.34). Equimolar amount of triflic acid results in the formation of N- ary I s u I fo n y I i n do I e s, whereas /V-arylsu Ifonylcar-bazoles are isolated in excess acid (Scheme 5.34). In the reaction sequence 1,4-butanedial formed in situ from 2,5-dimethoxytetrahydrofurane reacts with the sulfonamide to give the pyrrole derivative (Paal-Knorr synthesis). Subsequently, one of the formyl groups of 1,4-butanal alkylates the pyrrole ring followed by a second, intramolecular alkylation (cyclialkylation) step. 

Snieckus reported a combination directed ortho-metalation (DoM)-RCM strategy for the synthesis of benzazepine, benzazocine, and benzannulated sulfonamide heterocycles <00SL1294> (Scheme 60). For example, the Boc-protected aniline (75) was sequentially allylated to give 76 which underwent RCM in excellent yield to give benzazepine 77. Use of similar methodology led to 78 and 79 starting from Y-methylbenzamide and p-tolylsulfonamide, respectively. 

Although folic acid is vital for human health, we don t have the enzymes to make it it s a vitamin, which means we must take it in our diet or we die. Bacteria, on the other hand, do make folic acid. This is very useful, because it means that if we inhibit the enzymes of folic acid synthesis we can kill bacteria but we cannot possibly harm ourselves as we don t have those enzymes. The sulfa drugs, such as sul-famethoxypyridazine or sulfamethoxazole, imitate p-aminobenzoic acid and inhibit the enzyme dihy-dropteroate synthase. Each has a new heterocyclic system added to the sulfonamide part of the drug. 

The synthesis of aza-oxa crown ethers is best accomplished by making carbon-nitrogen bonds in the cyclisation step. Although the original syntheses operated under conditions of high dilution and involved the co-condensation of a diamine with a diacid chloride, these methods have been supplanted by the more versatile and convenient A-alkylation pathways involving toluene-sulfonamide or TV-benzyl intermediates. This chapter has focused on the metal-free synthesis of saturated aza-oxa crown ethers. There are a large number of examples of the synthesis of aromatic and heterocyclic aza-oxa crown ethers that involve the co-condensation of aldehydes and amines mediated by metal ions such as Pb2+ and Ba2+24,25 This in situ synthetic... 

Folic acid is a pteridine derivative (rings A and B constitute the pteridine heterocyclic system) synthesized by bacteria from GTP, p-aminobenzoic acid, and glutamic acid. Accordingly. the structure of folic acid is compased of three moieties the pteridine moiety derived from GTP. the p-aminobcnzoic acid moiety, and the glutamic acid moiety. (Antibacterial sulfonamides [see Chapter 8 compete with p-aminobenzoic acid and, thereby, interfere with bacterial folic acid synthesis.) Humans cannot synthesize folic acid. 

Carbonyldiimidazole has been used in a combinatorial synthesis of 2f/-benzo-l-thia-2,4-diazine-3(4//)-one 1,1-dioxides polymer-supported sulfonamides 246 react to produce the corresponding heterocycles, which are cleaved from the support using trifluoroacetic acid to give 85-96% of the A -2-aryl-2i/-benzo-l-thia-2,4-diazine-3(4//)-one 1,1-dioxides 247 (R = H, CF3, OMe) in 91% to >95% purity, as determined by HPLC (Equation 59) <2003JC073>. Further chemistry of the l-thia-2,4-diazine heterocycle on the polymer support has been discussed in Section 9.05.6.2.2. 

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