Efficient Synthesis of 1,4-Diaryl-5-methyl-1,2,3-triazole, A Potential mGluR1 Antagonist, and the Risk Assessment Study of Arylazides

Abstract

A concise and practical synthesis of a 1,4-diaryl-5-methyl-1,2,3-triazole is described. A mGluR1 antagonist 1 was prepared with one-pot operation by the Negishi coupling reaction between two building blocks, 5-bromophthalimidine (2) and 1-aryl-5-methyl-4-triazolylzinc (3-Zn ). Bromide 2 was synthesized via N-selective cyclization of o-hydroxymethylbenzamide 8 easily prepared from phthalide 4. Zinc species 3-Zn was generated in situ by transmetalation of 1-aryl-4-magnesio-5-methyltriazole (3-Mg ), which in turn was generated by the regioselective click chemistry between 2,4-difluorophenylazide (5) and propynylmagnesium bromide. The risk assessment of potentially explosive arylazides is also mentioned.

An Enolate‐Mediated Organocatalytic Azide–Ketone [3+2]‐Cycloaddition Reaction: Regioselective High‐Yielding Synthesis of Fully Decorated 1,2,3‐Triazoles

“…With applications in mind, we have prepared a few more 1,4,5‐trisubstituted‐1,2,3‐triazoles 4 pb and 4 pt – pv from the treatment of 2‐naphthylacetone 1 p with aryl azides C 6 H 5 N 3 ( 2 b ), 2,3‐F 2 C 6 H 3 N 3 ( 2 t ), 2,4‐F 2 C 6 H 3 N 3 ( 2 u ), and 3‐azido‐2‐bromopyridine ( 2 v ) at 25 °C for 0.5 h under 3 e catalysis (entries 15–18). The compounds 4 pb and 4 pt – pv are analogues of PET ligands for imaging mGluR1 C 2c–e. Surprisingly, there is no triazole formation from the reaction of benzylacetone 1 q with 2 a under 3 e or 3 i catalysis (entry 19).…”

“…The versatility of the OrgAKC reaction was further exemplified by synthesizing medicinally and materially useful compounds 4 su , 4 aw , and 4 bw (Scheme ) 2c–e. As shown in Scheme B, mGluR1 antagonist triazole 4 su ( A ) was synthesized in very good yield with a single isomer from the arylacetone 1 s and 2,4‐F 2 C 6 H 3 N 3 2 u under the metal‐free 3 e ‐catalysis at ambient conditions.…”

Synthesis and Structural Diversity of ZnCl2 and Zn(C6F5)2 Complexes of a Phosphinimine Ligand

“…ZnCl 2 , Zn(C 6 F 5 ) 2 , and ZnEt 2 were purchased from commercial sources in high purity and used without additional purification. L Dipp was prepared as previously reported,7e while MesN 3 14 and 4‐(diphenylphosphanyl)dibenzofuran15 were prepared by the standard literature methods. NMR spectra [ 1 H (300.13 MHz), 13 C{ 1 H} (75.47 MHz), 31 P{ 1 H} (121.48 MHz), 19 F (282.42 MHz), and 11 B (96.29 MHz)] were collected with a Bruker Avance II NMR spectrometer equipped with a variable‐temperature unit.…”

Hydrazoic Acid and Azides

“…Aromatic diazonium salts react with azide ions via pentazoles to (shock sensitive) aryl azides [92,103]:…”