Synlett
DOI: 10.1055/s-0040-1720474
letter
EuCheMS Organic Division Young Investigator Workshop

Copper-Catalyzed Alkynylation of Benzylic C–H Bonds with Alkynylboronic Esters

Mikkel B. Buendia
a  Department of Chemistry, Technical University of Denmark, Kemitorvet 207, 2800 Kgs. Lyngby, Denmark
,
Jan-Georges J. Balin
a  Department of Chemistry, Technical University of Denmark, Kemitorvet 207, 2800 Kgs. Lyngby, Denmark
,
a  Department of Chemistry, Technical University of Denmark, Kemitorvet 207, 2800 Kgs. Lyngby, Denmark
,
Zhong Lian
b  Department of Dermatology, State Key Laboratory of Bio-therapy and Cancer Center, West China Hospital and West China School of Pharmacy, Sichuan University, Chengdu 610041, P. R. of China
,
a  Department of Chemistry, Technical University of Denmark, Kemitorvet 207, 2800 Kgs. Lyngby, Denmark
› Author Affiliations
S.K. is deeply appreciative of financial support from the Lundbeck Foundation (grant no. R250-2017-1292), the Independent Research Fund Denmark (grant no. 0171-00018B), and the Villum Foundation (grant no. 35812). Z.L. thanks the National Natural Science Foundation of China (21901168), the ‘1000-Youth Talents Plan’, Sichuan Science and Technology Program (2021YJ0395), and Sichuan University for generous financial support.


Abstract

We report a simple method for copper-catalyzed benzylic C–H alkynylation that uses alkynylboronic esters as nucleophilic coupling partners. The catalytic system is readily available and the reaction takes place under mild conditions. Different substrates for the C–H functionalization, as well as various alkynylboronic ester nucleophiles, were evaluated. Finally, three examples of enantioselective C–H alkynylations are presented.

Supporting Information



Publication History

Received: 04 February 2021

Accepted after revision: 24 March 2021

Publication Date:
14 April 2021 (online)

© 2021. Thieme. All rights reserved

Georg Thieme Verlag KG
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  • 10 Trimethyl[3-(1-naphthyl)but-1-yn-1-yl]silane (4a); Typical Procedure In an argon-filled glovebox, a 4 mL vial was charged with CuOAc (1.2 mg, 0.010 mmol; 5 mol%), dtbbpy (3.2 mg, 0.012 mmol; 6 mol%), and Li2CO3 (29.6 mg, 0.400 mmol; 2.00 equiv). Benzene (1.6 mL) [CAUTION: carcinogen] was added followed by DMA (0.4 mL), and the mixture was stirred for 30 min. Then, 1-ethylnaphthalene (2a) (31.0 μL, 0.200 mmol; 1.00 equiv) and alkynylboronic ester 3a (62.8 mg, 0.280 mmol; 1.40 equiv) were added, and the mixture was stirred. After one minute, NFSI (126.1 mg, 0.400 mmol; 2.00 equiv) was added with stirring. The vial was sealed with a Teflon-lined screw cap and removed from the glovebox. Outside the glovebox, the mixture was stirred in an aluminum block at 30 °C for 16 h. The reaction was then quenched by filtration through silica gel with pentane and the mixture was concentrated in vacuo. The residue was purified by column chromatography (silica gel, pentane) to give a colorless oil; yield: 32 mg (63%). 1H NMR (400 MHz, CDCl3): δ = 8.12 (d, J = 8.3 Hz, 1 H), 7.89 (dd, J = 7.9, 1.6 Hz, 1 H), 7.78 (d, J = 7.7 Hz, 2 H), 7.62–7.45 (m, 3 H), 4.57 (q, J = 7.1 Hz, 1 H), 1.66 (d, J = 7.1 Hz, 3 H), 0.22 (s, 9 H). 13C NMR (101 MHz, CDCl3): δ = 138.7, 133.9, 130.5, 128.9, 127.4, 125.9, 125.7, 125.5, 124.3, 123.1, 109.7, 86.6, 29.5, 23.6, 0.2 (3 C). MS (EI): m/z [M +] calcd for C17H20Si: 252; found: 252.
  • 11 The absolute configuration of (R)-4a was determined by comparison of peak orders in chiral HPLC with those reported by Liu and co-workers (ref. 7), as well as by comparison of the optical rotation after TMS deprotection with the value reported in ref. 7.