Magnesium-Catalyzed N2-Regioselective Alkylation of 3-Substituted Pyrazoles
Received: 18 June 2019
Accepted after revision: 26 July 2019
09 August 2019 (online)
Published as part of the ISySyCat2019 Special Issue
A highly regioselective Mg-catalyzed alkylation of 3-substituted pyrazoles has been developed to provide N2-alkylated regioisomers. Using α-bromoacetates and acetamides as alkylating agents, this new method was applied to a variety of 3-substituted and 3,4-disubstituted pyrazoles to produce the N2-alkylated products with high regioselectivities ranging from 76:24 to 99:1 and 44–90% yields.
References and Notes
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- 10 Alkylation side products of DBU and Et3N with 2-bromo-N,N-dimethylacetamide were observed by LC-MS.
- 11 Representative Procedure (Conditions A)In a glovebox filled with N2 (≤0.1 ppm O2, ≤0.1 ppm H2O) were charged 3-phenyl-1H-pyrazole (200 mg, 1.39 mmol, 100 mol%) and MgBr2 (51.0 mg, 0.277 mmol, 20 mol%) into a vial equipped with a magnetic stir bar. THF (3.00 mL) and 2-bromo-N,N-dimethylacetamide (461 mg, 2.77 mmol, 200 mol%) were then added. i-Pr2NEt (377 mg, 2.91 mmol, 210 mol%) was added to the solution dropwise at 25 °C. The resulting mixture was stirred at 25 °C for 2 h. The reaction was quenched with saturated NH4Cl in MeOH (2 mL), and the resulting solution was concentrated to dryness. Water (1 mL) was then added to the residue which was extracted with i-PrOAc (4 × 1 mL). The crude product was loaded on to silica gel column and eluted with heptane/i-PrOAc to give compound 2-N2 (239 mg, 75% yield as a white solid. 1H NMR (400 MHz, CDCl3): δ = 7.59 (s, 1 H), 7.51–7.34 (m, 5 H), 6.34 (s, 1 H), 4.93 (s, 2 H), 2.98 (d, J = 8.0 Hz, 7 H). 13C NMR (101 MHz, CDCl3): δ = 167.03, 145.02, 139.73, 130.78, 129.13, 128.81, 128.77, 106.43, 50.94, 36.65, 36.05. HRMS: m/z calcd for C13H16N3O [M + H]+: 230.1288; found: 230.1287.
- 12 Some strongly electron-deficient pyrazoles like 3a led to over-alkylated products. The side reaction was minimized by performing the reaction at 0 °C (Figure 2).
- 13 Using 20 mol% MgBr2, 3f-N2 and 3g-N2 were formed in regioselectivities of 89:11 (53% conversion) and 79:21 (100% conversion), respectively.