Designing Homogeneous Copper-Free Sonogashira Reaction through a Prism of Pd–Pd Transmetalation

Simultaneous introduction of two different palladium (pre)catalysts, one tuned to promote oxidative addition to (hetero)aryl bromide and another to activate terminal alkyne substrate, leads to productive Pd–Pd transmetalation, subsequent reductive elimination, and formation of disubstituted alkyne. This conceptually novel rational design of copper-free Sonogashira reaction enabled facile identification of the reaction conditions, suitable for the synthesis of alkyl, aryl, and heteroaryl substituted alkynes at room temperature with as low as 0.125 mol % total Pd loading.

Palladium oxidative adducts 4a and 4b were prepared using standard Schlenk line techniques.
Melting points were determined on a Kofler micro hot stage and are uncorrected.
IR spectra were obtained with a Perkin-Elmer Spectrum 100, equipped with a Specac Golden Gate Diamond ATR as a solid sample support.
Proton spectra were recorded in CDCl3 and DMSO-d6 and are referenced to the residual signals of CHCl3 (at δ 7.26 ppm) and DMSO-d5 (at δ 2.50 ppm). Carbon chemical shifts are given against the central line of the solvent signal: CDCl3 (at δ 77.16 ppm), DMSO-d6 (at δ 39.52 ppm). 19 F NMR and 11 B NMR spectra were referenced to CCl3F and 15% BF3 etherate in CDCl3, respectively, as external standards at δ 0. 31 P NMR spectra were referenced to external 85% phosphoric acid (at δ 0 ppm) and were acquired with a Bruker 31 P composite Analytical thin-layer chromatography (TLC) was carried out on Fluka Silica Gel TLC cards, visualized with a UV lamp (254 nm and/or 366 nm).
Purification of products was achieved by column chromatography using silica gel 60N.

Preparation of palladium complex Pd-PyMIC
Palladium complex Pd-PyMIC was prepared by the previously reported procedure. 1

Formation of enyne-like side products in phosphine ligand screening experiments (Table 1, L1-L3)
Procedure: An oven-dried (130 °C for 3 hour) 5 mL round-bottom flask, equipped with magnetic stir bar and septum, was charged with acetonitrile (1 mL), (PhCN)2PdCl2 (0.04 mmol, 2 mol %) and ligand L (0.08 mmol, 4 mol %) under continuous flow of argon. The reaction mixture was stirred for 5 min at room temperature, then Pd-PyMIC (0.02 mmol, 1 mol %), DABCO (2.8 mmol, 1.4 equiv), 4-bromotoluene (1a, 2 mmol) and phenylacetylene (2a, 2.8 mmol, 1.4 equiv) were added. The argon flow was removed and the reaction mixture was stirred at room temperature for 24 hours. The conversions were determined by 1 H NMR of aliquots (20 µL) of the crude reaction mixture, dissolved in CDCl3 (0.7 mL). Each experiment was performed at least in duplicate and the results are collected in Table 1 and Figure S1. Selected regions of 1 H NMR spectra of a) alkyne 2a, b) bromide 1a, c) crude reaction mixture using L1 as a ligand, d) crude reaction mixture using L2 as a ligand, e) crude reaction mixture using L3 as a ligand, and f) tolane 3a in CDCl3, 500 MHz. Table S1  1.4 equiv) were added. Argon flow was removed and the reaction mixture was stirred at room temperature for the time indicated below and in Table 3, during which milky, yellowish to brownish coloured mixture started forming. After completion the reaction mixture was diluted with ethyl acetate (150 mL) and washed with brine (2  100 mL). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated by rotary evaporation to give a crude brown solid/oil. Product 3 was additionally purified by SiO2 column chromatography.  Table 3, during which milky, yellowish to brownish coloured mixture started forming. After completion the reaction mixture was diluted with ethyl acetate (150 mL) and washed with brine (2  100 mL). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated by rotary evaporation to give a crude brown solid/oil. Product 3 was additionally purified by SiO2 column chromatography.

Synthesis and characterization of palladium oxidative adducts 4
Compounds 4a and 4b were prepared by a modified literature procedure.    Figures S39 and S40).