Solid-Phase Synthesis of NH-1,2,3-Triazoles Using 4,4′-Bismethoxybenzhydryl Azide

Abstract

Readily available 4,4′-bismethoxybenzhydryl azide was found to be a useful building block for the synthesis of NH-1,2,3-triazoles through copper(I)-catalyzed cycloaddition reactions with solid-supported terminal alkynes, followed by acid-mediated deprotection. Peptide-containing NH-1,2,3-triazoles were obtained in good yield and excellent purity (typically >95%).

Key words

click chemistry - NH-1,2,3-triazoles - solid-phase synthesis - cross-coupling - azide

• References and Notes

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• 14 General Experimental Procedure for the Synthesis of Terminal Alkynes on Solid Support; Sonogashira Cross-Coupling/TMS Deprotection (8–10, 13 and 14): Iodoaryl-functionalized resins (1 equiv) were swollen in DMF and degassed with a stream of Ar for 20 min. CuI (0.5 equiv), DIEA (50 equiv), TMS-acetylene (10 equiv), and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) (0.1 equiv) were added, and the reaction vessel was sealed before shaking for 24 h at r.t. The resin was then transferred to a flat-bottomed PE-syringe fitted with a PPE filter and washed with MeOH (6 ×), pyridine (6 ×), DMF (6 ×), MeOH (6 ×) and CH₂Cl₂ (6 ×). Deprotection of the TMS group was achieved by addition of TBAF (4 equiv, 1 M in THF) and AcOH (4.5 equiv) to the resin preswollen in THF. The mixture was allowed to react for 1 h, upon which the resin was washed with DMF (6 ×) and CH₂Cl₂ (6 ×). The resin was lyophilized to remove all traces of solvent. The product was cleaved off the resin by treatment with 0.1 M NaOH (aq) for 2 h, followed by neutralization with 0.1 M HCl (aq) and washings with MeCN (4 ×) and CH₂Cl₂ (2 ×). Evaporation of all volatiles in vacuo provided the crude products. Terminal Alkyne 8: ¹H NMR (400 MHz, DMSO-d ₆): δ = 12.58 (s, 1 H), 8.71 (d, J = 8.6 Hz, 1 H), 8.44 (t, J = 5.8 Hz, 1 H), 7.79 (d, J = 8.3 Hz, 2 H), 7.54 (d, J = 8.3 Hz, 2 H), 7.35 (d, J = 7.3 Hz, 2 H), 7.24 (t, J = 7.5 Hz, 2 H), 7.15 (t, J = 7.3 Hz, 1 H), 4.70–4.79 (m, 1 H), 4.36 (s, 1 H), 3.74–3.87 (m, 2 H), 3.15 (dd, J = 13.7, 3.5 Hz, 1 H), 2.98 (dd, J = 13.7, 11.4 Hz, 1 H). ¹³C NMR (100 MHz, DMSO-d ₆): δ = 171.7, 171.1, 165.4, 138.5, 134.1, 131.5 (2 × C), 129.1 (2 × C), 128.1 (2 × C), 127.7 (2 × C), 126.2, 124.5, 82.9 (2 × C), 54.8, 40.8, 37.1. MS (ESI): m/z [M + H]⁺ calcd for C₂₀H₁₉N₂O₄: 351.1; found: 351.4. Purity (RP-UPLC): >95%.
• 15 General Experimental Procedure for the Synthesis of NH-1,2,3-Triazoles on Solid Support; CuAAC–Bismethoxybenzhydryl Deprotection (5, 11, 12, 15–20): Alkyne-functionalized resins (1 equiv) were swollen in a mixture of NMP and H₂O (4:1). A solution of 2,6-lutidine (2 equiv), azide 1 (2 equiv), CuI (1 equiv), and sodium ascorbate (1 equiv) in NMP–H₂O (2:1) was added, and the reaction vessel was sealed before shaking for 24 h at r.t. The resin was then washed with pyridine (6 ×), DMF (6 ×) and CH₂Cl₂ (6 ×). Removal of the 4,4′-bismethoxybenzhydryl group was achieved by treatment of the resin with 50% TFA–CH₂Cl₂ (2 × 30 min), followed by washings with 20% piperidine in DMF (2 × 5 min), DMF (6 ×) and CH₂Cl₂ (6 ×). The crude products were cleaved off the resin according to the procedure described above. NH-1,2,3-Triazole 11: ¹H NMR (300 MHz, DMSO-d ₆): δ = 8.99–9.26 (br s, 1 H), 8.74 (d, J = 8.7 Hz, 1 H), 8.53 (t, J = 5.8 Hz, 1 H), 7.87–7.97 (m, 4 H), 7.37 (d, J = 7.1 Hz, 2 H), 7.24 (t, J = 7.3 Hz, 2 H), 7.14 (t, J = 7.2 Hz, 1 H), 4.71–4.81 (m, 1 H), 3.82 (dd, J = 3.2, 5.7 Hz, 2 H), 3.17 (dd, J = 3.8, 13.6 Hz, 1 H), 3.01–3.08 (m, 1 H). MS (ESI): m/z [M + H]⁺ calcd for C₂₀H₂₀N₅O₄: 394.2; found: 394.3. Purity (RP-UPLC): >95%