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DOI: 10.1055/s-0039-1690160
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© Georg Thieme Verlag Stuttgart · New York

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

Di Xu
a  Department of Small Molecule Process Chemistry, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA   Email: xud19@gene.com
,
Lena Frank
a  Department of Small Molecule Process Chemistry, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA   Email: xud19@gene.com
,
Tina Nguyen
b  Department of Small Molecule Analytical Chemistry, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA
,
Andreas Stumpf
a  Department of Small Molecule Process Chemistry, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA   Email: xud19@gene.com
,
David Russell
b  Department of Small Molecule Analytical Chemistry, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA
,
Remy Angelaud
a  Department of Small Molecule Process Chemistry, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA   Email: xud19@gene.com
,
Francis Gosselin
a  Department of Small Molecule Process Chemistry, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA   Email: xud19@gene.com
› Author Affiliations
Further Information

Publication History

Received: 18 June 2019

Accepted after revision: 26 July 2019

Publication Date:
09 August 2019 (eFirst)

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.

Supporting Information

 
  • 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.