Additive-Free Copper-Catalyzed Benzylic C(sp³)–H Carbamation: Simple Preparation of Primary Benzylic Amines

Abstract

A simple and practical method for the synthesis of primary alkylamines by direct functionalization of hydrocarbons is described. The N-Boc-protected alkylamines are readily prepared from tert-butyl (trimethylsilyl)carbamate and N-fluorobenzenesulfonimide in the presence of a Cu(I) catalyst at low catalyst loadings. Advantageously, this process proceeds free of any additive such as auxiliary bases/acids, requires only one equivalent of the substrate, and does not require ligand synthesis. This operationally simple C–H carbamation method shows high site selectivity and good functional-group tolerance, and uses a commercially available Cu precatalyst and oxidant to furnish N-Boc protected alkylamines in yields of 16–83%. The products can be simply deprotected under mild acidic conditions to generate primary benzylic amines. This practical method was subsequently used for the synthesis of the active pharmaceutical ingredients cinacalcet and sertraline.

Key words

copper catalysis - fluorobenzenesulfonimide - amination - alkylamines - benzylic amines

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• 43 Copper-Catalyzed Benzylic C–H Carbamation; General Procedure On the benchtop, a disposable 4 mL glass vial equipped with a Teflon-coated stirrer bar was charged with TMSNHBoc (0.5 mmol, 95 mg, 2 equiv) and NFSI (0.75 mmol, 236.5 mg, 2.5 equiv). Solid R–H substrates (0.25 mmol, 1 equiv) were weighed and added to the vial. The vial was then sealed with a PTFE-lined pierceable cap. BOX (L1; 0.015 mmol, 4.5 mg, 6 mol%) was weighed into a second vial equipped with a Teflon stirrer bar. Both vials were then transferred to a purged glovebox under an atmosphere of dry N₂. In the glovebox, CuI·Me₂S (0.018 mmol, 4.5 mg, 5 mol%) was weighed into the vial containing the BOX ligand, and MeCN (2.0 mL) and the R–H substrate (if liquid) were added. The mixture was then stirred for 30 min under N₂ to form a dull-purple Cu catalyst solution. This was then added to the vial containing the other reaction components, and the mixture was stirred at 40 °C for 24 h.
• 44 tert-Butyl (5-Methyl-2,3-dihydro-1H-inden-1-yl)carbamate (2l) Prepared by the general procedure, with purification by flash column chromatography (silica gel, 0–20% gradient EtOAc–hexanes) to give a white solid; yield: 53 mg (76%). ¹H NMR (400 MHz, CDCl₃): δ = 7.21 (d, J = 7.6 Hz, 1 H), 7.02 (d, J = 11.0 Hz, 2 H), 5.13 (q, J = 7.8 Hz, 1 H), 4.78 (d, J = 8.8 Hz, 1 H), 2.90 (ddd, J = 16.0, 8.8, 3.9 Hz, 1 H), 2.78 (dt, J = 16.1, 8.1 Hz, 1 H), 2.62–2.44 (m, 1 H), 2.33 (s, 3 H), 1.85–1.71 (m, 1 H), 1.49 (s, 9 H). ¹³C NMR (121 MHz, CDCl₃): δ = 155.8, 143.5, 140.8, 137.7, 127.6, 125.5, 123.9, 79.4, 55.8, 34.6, 30.1, 28.7, 21.4. GC/MS (EI): m/z = 247.1. HRMS (TOF-ESI): m/z [M + 1]⁺ calcd for C₁₅H₂₃NO₂: 248.1651; found: 248.1657.