Understanding Six-Membered NHC-Copper(I) Allylic Borylation Selectivity by Comparison with other Catalysts and Different Substrates

^◊These authors contributed equally to this work

Abstract

We recently introduced a family of 6-NHC-Cu(I) catalysts that exhibit highest selectivities (regio- and enantio-) exclusively when aryl ethers are used as the leaving group. Understanding the match ­between a catalyst and leaving group remains elusive. We sought to increase our understanding of this system by comparing our catalyst’s ­activity with other catalysts using substrates that contain different leaving groups. Our objective is to better understand the regioselectivity–leaving group combinations. We also observed that our catalyst functioned best when methanol was used as an additive. We examined the selectivities as a function of other protic additives. Finally, we wanted to understand the regioselectivity–enantioselectivity relationship with regards to internal versus terminal leaving groups. Overall, we demonstrate that matching leaving group and catalyst is important and that for our extended aromatic ligand the use of aromatic leaving groups is a unique pairing. We also demonstrate that the leaving group is also critical for controlling both types of selectivity.

Key words

N-heterocyclic carbenes - copper catalyst - regioselectivities - enantioselectivities - allylic borylation

• References and Notes

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• 14 General Procedure for Asymmetric Allylic Borylations Using the NHC-CuCl Catalysts in Table [1] NHC-copper catalyst (0.02 equiv, 0.004 mmol) was loaded into a flame-dried Schlenk tube. Anhydrous diethyl ether (0.1 mL) was added to the reaction tube, and the suspension was stirred and cooled to –50 °C. NaOtBu (0.3 equiv), MeOH (2 equiv), and bis(pinacolato)diboron (1.5 equiv) were added in order, and the reaction mixture was stirred for 10 min. Allyl ether (1 equiv, 0.2 mmol) was added, and the reaction mixture was stirred at –50 °C. The resulting mixture was filtered through short Celite pad and washed with diethyl ether. The filtrate was concentrated under reduced pressure. For the determination of regioselectivity, ¹H NMR was measured with crude product. For the determination of enantioselectivity, the resulting crude material was dissolved in ethyl acetate (2 mL) and oxidized by treatment of H₂O₂ (5 equiv) and 1 M NaOH aqueous solution (2 equiv). After stirring for 1 h, the mixture was quenched by water. The organic layer was extracted with ethyl acetate and evaporated in vacuo. The crude alcohol product was separated by preparative TLC for the HPLC measurement. Branched Boronate Product ¹H NMR (600 MHz, CDCl₃): δ = 7.28–7.25 (m, 2 H), 7.19–7.15 (m, 3 H), 5.82 (ddd, J = 17.1, 10.2, 8.3 Hz, 1 H), 5.04–4.99 (m, 2 H), 2.68–2.63 (m, 1 H), 2.59-2.54 (m, 1H), 1.90–1.86 (m, 2 H), 1.76–1.72 (m, 1 H), 1.24 (s, 12 H) ppm. All the resonances in the spectra were in accordance with reported values. Linear Boronate Product ¹H NMR (600 MHz, CDCl₃): δ = 7.28–7.24 (m, 2 H), 7.21–7.15 (m, 3 H), 5.54–5.43 (m, 2 H), 2.66 (td, J = 7.8, 4.1 Hz, 2 H), 2.36–2.28 (m, 2 H), 1.65 (t, J = 7.0 Hz, 2 H), 1.24 (s, 12 H) ppm. All the resonances in the spectra were in accordance with reported values. Reduction Product ¹H NMR (600 MHz, CDCl₃): δ = 7.30–7.28 (m, 2 H), 7.21–7.18 (m, 3 H), 7.06 (t, J = 8.0 Hz, 1 H), 6.34 (dd, J = 8.2, 2.3 Hz, 1 H), 6.31 (dd, J = 7.8, 2.1 Hz, 1 H), 6.26 (s, 1 H), 5.90–5.84 (m, 1 H), 5.77–5.72 (m, 1 H), 4.43 (dd, J = 5.9, 1.3 Hz, 2 H), 2.73 (dd, J = 9.1, 6.7 Hz, 2 H), 2.49–2.36 (m, 2 H) ppm. ¹³C NMR (151 MHz, CDCl₃): δ = 160.0, 156.6, 147.7, 141.8, 134.4, 130.3, 130.2, 128.5, 128.4, 126.0, 125.7, 122.0, 115.8, 110.6, 108.2, 105.1, 102.1, 68.6, 35.5, 34.2 ppm. HRMS-ESI: m/z calcd for [C₁₇H₁₉NO + H]⁺ : 254.1545; found: 254.1556.
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• 17 Followed general reaction protocol in ref. 14 except that 1 mol% of NHC-Cu complex 4 was used. Reaction mixture was stirred at –50 °C for 16 h.