Magnesium-Catalyzed N2-Regioselective Alkylation of 3-Substituted Pyrazoles

Published as part of the ISySyCat2019 Special Issue

Abstract

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.

Key words

pyrazole - alkylation - magnesium - catalysis - regioselectivity

• References and Notes

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• 7 Anhydrous Lewis acid catalysts were used. No conversion was observed with addition of 100 mol% water.
• 8 The impact of the Mg counterions on regioselectivity and yield were also tested (see Supporting Information, Table S1). Although the N2 isomer was formed selectively in all cases, catalysts with less dissociating counterions⁹ provided superior regioselectivity. MgBr₂ provided the best compromise between yield and regioselectivity and was thus selected as the catalyst of choice.
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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.