Zinc Mediated Azide–Alkyne Ligation to 1,5- and 1,4,5-Substituted 1,2,3-Triazoles

A mild method for regioselective formation of 1,5-substituted 1,2,3-triazoles is described. The zinc-mediated reaction works at room temperature and is successful across a wide range of azido/alkynyl substrates. Additionally, the triazole 4-position can be further functionalized through the intermediate aryl-zinc to accommodate a diverse three-component coupling strategy.

Experimental 1 H-NMR spectra were recorded on 500, 400 or 300 Bruker spectrometers with residual chloroform or DMSO as the internal reference (CHCl 3 , δ H = 7.26 ppm; DMSO, δ H = 2.50 ppm). 13 C-NMR spectra used the central resonance of CDCl 3 or DMSO as the internal reference (CDCl 3 , δ C = 77.0 ppm; DMSO, δ C = 39.5 ppm). 19 F-NMR spectra are measured relative to CFCl 3 δ F = 0.0 (external reference). Assignments were made using a range of NMR experiments (DEPT135, COSY, HMQC and HMBC). All chemical shifts are quoted in parts per million (ppm) down field from tetramethylsilane, measured from the centre of the signal except in the case of multiplets of more than one proton which are quoted as a range. Coupling constants are quoted to the nearest 0.5 Hz. Splitting patterns are abbreviated as follows: singlet (s), doublet (d), triplet (t), quartet (q), quintet (quin.), sextet (sex.), septet (sept.), multiplet (m), apparent ( ap. ), broad ( br.) and combinations thereof.
Infrared spectra were recorded on a Perkin-Elmer Spectrum One FT-IR spectrometer as a thin film and are reported in cm -1 . Letters in parentheses refer to the relative absorbency of the main peak: w, weak, < 40%; m, medium, 41-74%; s, strong >75%; and br, broad.
Melting points were determined using a Büchi M-565 melting point apparatus.
LCMS analysis was performed on an Agilent HP 1100 chromatograph (Atlantis RP column) attached to an HPLC/MSD mass spectrometer (API-ES). Elution was carried out using a reversedphase gradient of MeOH:i-PrOH (9:1) / water, with both solvents containing 0.2% formic acid. The gradient of the 6.0 min run is described in Table 1. All THF was distilled under N 2 over sodium wire and benzophenone. Toluene and dichloromethane were distilled under N 2 and over calcium hydride. All reagents were used as obtained from commercial sources.

Starting Materials
Azides CAUTION: Azides are both shock sensitive and toxic. The use of acids in the presence of the azide ion is advised against due to the possible release of hydrazoic acid gas, a known poison. Furthermore, the use of CH 2 Cl 2 in the presence of the azide ion may lead to the formation of diazidomethane (N 3 CH 2 N 3 ) which is known to self detonate. No incidents occurred during the synthesis or use of azides but for these reasons the reactions were not performed on scales greater than 5 g.
Benzyl azide was synthesised using known procedures. 1 General procedure for the synthesis of aromatic azides from their corresponding anilines. 2 A solution of the aniline (5 mmol) was dissolved in MeCN (25 mL), azidotrimethylsilane (6 mmol) was added before cooling to 0 °C. tert-Butyl nitrite (5.5 mmol) was added portion wise over 15 minutes to the solution. The reaction was allowed to warm to ambient temperature and stirred until complete by HPLC, typically 2 hours. The solvent was removed in vacuo and the crude material was purified by passing through a plug of silica and eluted with CH 2 Cl 2 .

Novel Starting Materials
Azide precursor to 3c

General Procedure for the Synthesis of 1,4-Substituted 1,2,3-Triazoles
The azide (1 mmol), alkyne (1.2 mmol) and N-methylimidazole (0.1 mmol, 8 mg) were added to a glass vial or round bottomed flask. The vessel was purged with N 2 and kept under a N 2 balloon. Dry THF (8 mL) was added to dissolve the starting materials before ZnEt 2 (1.5 mmol, 1.5 mL, 1 M in hexanes) was added in 2 portions over 5 minutes. The reaction was stirred at ambient temperature overnight (approximately 18 hours) before quenching with sat. NH 4 Cl (aq) (20 mL) -Cautionethane gas is evolved at this stage. The mixture was partitioned between water (20 mL) and EtOAc (40 mL) and the organic layer was washed with water (20 mL), dried with Na 2 SO 4 , filtered and concentrated in vacuo. The crude material was dry loaded onto silica gel before purification by column chromatography (silica gel, EtOAc/hexane) to afford the pure material. (3a)
The crude material was dry loaded onto silica gel before purification by column chromatography (silica gel, EtOAc/hexane) to afford a brown oil (71%).