Copper‐Free Solid‐Phase Synthesis of Triazolo[1,5‐a][1,4]diazepin‐6‐ones

Abstract

Synthesis of triazolo[1,5‐a][1,4]diazepin‐6‐ones on solid support is reported in this article. Amino acids immobilized on Wang resin were nosylated and alkylated with propargyl alcohol, but‐2‐yn‐1‐ol or different 3‐phenylprop‐2‐yn‐1‐ols using Mitsunobu alkylation conditions. After denosylation, acylation with Fmoc‐azidoalanine yielded linear precursors that were thermally cyclized on resin to give immobilized triazolodiazepinones. After cleavage from the polymer support, the target compounds were obtained in high crude purities and good overall yields. Furthermore, the synthetic approach was applied to convenient solid‐phase synthesis of oligopeptide containing the triazolodiazepinone moiety as the peptidomimetic heterocyclic constraint.

p‐TSA‐Mediated Four‐Component Reaction: One‐Step Access to Mesoionic 1H‐Imidazol‐3‐ium‐4‐olates, Direct NHC Precursors

“… [a] HPLC purity of the crude product calculated from HPLC‐UV traces at 220–500 nm. [b] Yield after purification by semipreparative HPLC. [c] Yield obtained by gravimetry. [d] Yield calculated from the 1 H NMR spectrum of the purified product [49,50] …”

Reagent-Based Diversity-Oriented Synthesis of Triazolo[1,5-a][1,4]diazepine Derivatives from Polymer-Supported Homoazidoalanine

“…In contrast to the previously used Fmoc-azidoalanine, Fmoc-homoazidoalanine (Fmoc-AHA) was the key synthon in the reaction sequence. Fmoc-AHA was prepared from Fmoc-glutamine in two steps using Hofmann rearrangement and catalytic diazotransfer .…”

“…On the other hand, despite the potential interference of an azide with triphenylphosphine, immobilization using Mitsunobu conditions was successful and furnished resin 1 with sufficient loading of Fmoc-AHA ranging from 0.21 to 0.37 mmol/g. The formation of the triazolodiazepine scaffold was accomplished according to a previously reported strategy (Scheme ): after Fmoc cleavage and the reaction with either 2-nitrobenzenesulfonyl chloride or 4-nitrobenzenesulfonyl chloride (2/4-Ns-Cls), the resulting sulfonamides were subjected to Mitsunobu alkylation with 3-phenylprop-2-yn-1-ol as the representative alkynol followed by catalyst-free Huisgen cycloaddition of resins 2a and 2b , which afforded key intermediates 3a and 3b .…”

“…The target N -hydroxy-spiro-indolines 6b – i were isolated in 54–90% crude HPLC purities and 19–60% overall yields using the procedures developed for 6a ; however, the reaction conditions had to be modified in some cases. Intermediate 3g (R 2 = 4-MeO) synthesized using 4-methoxy-2-nitrobenzenesulfonyl chloride required a longer reaction time for the sulfonylation step, and furthermore, its C -arylation to 4g proceeded only when heated to 50 °C for 2 h. The Huisgen reaction of resin 3h (R 2 = 4-Cl) was relatively slow, and compared to the previously reported 24–48 h, it required 4 days to reach completion. Catalytic hydrogenation of 5h (R 2 = 4-Cl) required 3 days.…”

“…In contrast to analogous triazolobenzodiazepinones, which have been prepared in different ways, − the synthesis of triazolodiazepines has rarely been reported. The original approach was published in 2011 by Buysse et al In our recent contribution, we have developed an alternative methodology based on solid-phase synthesis (SPS), starting from immobilized amino acids and using Fmoc-azidoalanine as the key building block. Variously substituted triazolodiazepine-6-ones were obtained by on-resin catalyst-free Huisgen reaction.…”