Diazomethane sulfonamide synthesis

Carbenes from Diazo Compounds. Decomposition of diazo compounds to form carbenes is a quite general reaction that is applicable to diazomethane and other diazoalkanes, diazoalkenes, and diazo compounds with aryl and acyl substituents. The main restrictions on this method are the limitations on synthesis and limited stability of the diazo compounds. The smaller diazoalkanes are toxic and potentially explosive, and they are usually prepared immediately before use. The most general synthetic routes involve base-catalyzed decomposition of V-nitroso derivatives of amides, ureas, or sulfonamides, as illustrated by several reactions used for the preparation of diazomethane. 

Because many more alcohols than alkyl halides are commercially available, the Mitsu-nobu reaction enables the synthesis of larger and more diverse compound arrays than alkylation with alkyl halides. A -AcyIsuIfonamides are strongly acidic and can be alkylated with diazomethane (Entry 6, Table 8.9) or trimethylsilyldiazomethane [137]. Resin-bound sulfonamides have been N-acylated by treatment with acyl halides, and N-carbamoylated by treatment with isocyanates [138]. 

The safety catch principle for the solid-phase preparation of C-ternninal modified peptides requires the bond between the handle and the first residue to be stable to the normal conditions of SPPS. However, at the end of the synthesis, a chennical transformation of the linker substituent makes the key bond labile to nucleophiles. The 4-sulfanylphenol 44b ti and the sulfonamide 45 (Kenner) resins are two examples of safety catch resins. Thus, in the first case, which is only compatible with the Boc/Bzl strategy, once the peptide chain is elongated, treatment of the peptide-resin with hydrogen peroxide converts the sulfide into the corresponding sulfone, which makes the bond labile to nucleophiles. In the second case, N-methylation with diazomethane leads to an N-methylated peptidyl-sulfonannide-resin, from which peptides can also be cleaved by nucleophiles. 

Safety-catch linker, a linker moiety handle) that is stable under the conditions of peptide synthesis, but must be activated for cleavage. The two chemical states of safety-catch linkers differ either by real orthogonality or by the kinetics of the cleavage reaction. The most popular safety-catch linkers are based on sulfonamides, where the first amino acid is anchored in the form of an N-acyl sulfonamide, which is stable towards acidic and basic reaction conditions. Upon N-alkylation of the N-acyl sulfonamide with either diazomethane or iodomethane, a secondary N-acyl... 

Later on, the authors focused on the continuous two-step synthesis of the diazomethane precursor N-methyl-N-nitroso-p-toluene sulfonamide (33) in micro-structured devices, as a proof-of-concept liberation of diazomethane from the reaction mixture was performed in a separate step [18]. 

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