Synthesis and stability of 3‐nitro‐2‐pyridinesulfenyl chloride (NpysCl)

Abstract

3‐Nitro‐2‐pyridinesulfenyl chloride (NpysCl) is the starting material for the synthesis of N‐, O‐ and S‐Npys‐protected amino acids. Two efficient, novel synthetic routes to NpysCl are described. The stability of NpysCl was determined in a variety of solvents, with and without base, to determine the most suitable solvent and base for the synthesis of N‐Npys amino acids. The syntheses of Npys‐Ala and Boc‐Lys(Npys) tert‐butylammonium salt are also described.

4‐Fluorophenyl 3‐nitro‐2‐pyridinesulfenate as a practical protecting agent for amino acids

“…Finally, to demonstrate the usefulness of Npys‐OPh( p F) ( 1 ), we examined its stability, both during storage and in solution. In previous reports, the conventional protecting reagent Npys‐Cl was reported to be stable for several months at 4°C in a closed container . However, in our study, NMR analysis showed that 25% of Npys‐Cl was converted to the dimer after 3 weeks under these conditions.…”

“…In previous reports, the conventional protecting reagent Npys-Cl was reported to be stable for several months at 4°C in a closed container. 11 However, in our study, NMR analysis showed that 25% of Npys-Cl was converted to the dimer after 3 weeks under these conditions. By contrast, no decomposition of our new reagent (1) was observed after 2 months at 4°C.…”

“…Moreover, 1 was stable at room temperature under shelf conditions for 1 day, after which it decomposed gradually to 58% of its starting amount after 7 days while Npys‐Cl decomposed to 72% of its starting amount (see Supporting Information, SI). We also evaluated the stability of 1 in dimethylsulfoxide, because the previous literature reported that Npys‐Cl was unstable in dimethylsulfoxide, 49% of Npys‐Cl decomposing during 20 hours . By contrast, 1 was stable for more than 20 hours.…”

“…As shown in Table 3, compound 1 successfully introduced an Npys group to the α-amino group of HCl·H-Ala-OtBu, and the corresponding product, Npys-Ala-OtBu (11), was obtained with a yield of 91% in 3 hours (entry 1). Compound 2 also protected the amino group of HCl·H-Ala-OtBu with an 82% yield but required a longer reaction time (6 hours) than compound 1 (entry 2).…”

“…To the best of our knowledge, Npys‐Cl is the only reagent that has been used to date for Npys protection. This sulfenyl chloride, however, has some obvious defects including instability with light or moisture and its tendency to dimerize, even at low temperatures, a major drawback in Npys protection strategy. Developed with a view to overcoming this, Npys‐OR compounds are known to be stable and very attractive Npys derivatives, and we have found that methyl 3‐nitro‐2‐pyridinesulfenate, an Npys‐OMe derivative could be obtained as a stable crystalline compound .…”