Design, Synthesis, and Validation of an Effective, Reusable Silicon-Based Transfer Agent for Room-Temperature Pd-Catalyzed Cross-Coupling Reactions of Aryl and Heteroaryl Chlorides with Readily Available Aryl Lithium Reagents

Abstract

A reusable silicon-based transfer agent (1) has been designed, synthesized, and validated for effective room-temperature palladium-catalyzed cross-coupling reactions (CCRs) of aryl and heteroaryl chlorides with readily accessible aryl lithium reagents. The crystalline, bench-stable siloxane transfer agent (1) is easily prepared via a one-step protocol. Importantly, this “green” CCR protocol circumvents prefunctionalization, isolation of organometallic cross-coupling partners, and/or stoichiometric waste aside from LiCl. DFT calculations support a σ-bond metathesis mechanism during transmetalation and lead to insights on the importance of the CF3 groups.

Design, Synthesis, and Application of Polymer-Supported Silicon-Transfer Agents for Cross-Coupling Reactions with Organolithium Reagents

“…The product was purified by chromatography on SiO 2 (20 % Et 2 O/hexanes) to afford 6f (39.0 mg, 0.207 mmol, 72 %) as a colorless oil. Analytical data matches that which has been previously reported for 6f : 8a 1 H NMR (500 MHz, CDCl 3 ) δ 7.31 – 7.26 (m, 2 H), 7.22 – 7.16 (m, 3 H), 6.22 (dd, J = 10.5, 15.1 Hz, 1 H), 6.09 (dd, J = 10.5, 15.1 Hz, 1 H), 5.79 – 5.70 (m, 2 H), 4.17 (d, J = 3.8 Hz, 2 H), 2.71 (t, J = 7.8 Hz, 2 H), 2.42 (q, J = 7.4 Hz, 2 H), 1.30 (bs, 1 H); 13 C NMR (125 MHz, CDCl 3 ) δ 141.8, 134.6, 132.0, 130.1, 130.0, 128.6, 128.5, 126.0, 63.7, 35.8, 34.6; HRMS (CI + ) m/z (M-OH) + : Calcd for C 13 H 15 : 171.1174, found: 171.1182.…”

“…Pleasingly, PNTA-I 200 proved to be a viable transfer agent in cross-coupling reactions employing conditions similar to those reported for the small molecule transfer agents 8 (Table 1). For example, use of 2.0 equiv of the siloxane polymer at a concentration of 15 mg/mL permitted cross-coupling between phenyllithium and 4-iodoanisole to furnish the desired product 6 , albeit with the formation of a small amount of undesired homocoupled product 7 (entry 1).…”

“…In connection with the evolution of Anion Relay Chemistry (ARC), 7 we recently demonstrated that siloxane 1 and analogues 8 thereof comprise competent recoverable silicon-based transfer agents for efficient palladium-catalyzed intermolecular cross-coupling reactions of aryl and alkenyl organolithium reagents at ambient temperature and pressure (Scheme 2). This tactic offers the solution to the intrinsic limitation of the Murahashi and importantly recent Feringa cross-coupling protocols 2,9 of organolithiums, which are not compatible with substrates bearing sensitive functional groups such as nitriles or carbonyl functionalities (i.e., ketones, aldehyde and/or esters).…”

“…Given that the siloxane-based transfer agents are fully regenerated following the CCRs, the siloxane-based method comprises an effective atom-economical approach for the construction of C - C bonds. The recovery of these transfer agents via either chromatographic separation or acid-base extraction, the latter by incorporation of a Brønsted base in the siloxane transfer structure, 8b however in some cases has proven less than optimal. The development of solid-supported transfer agents hold the promise of significantly simplifying product purification, and thereby providing an attractive and practical method for recycling of transfer agents, further advancing the siloxane-based cross-coupling tactic (e.g., a polymer with attached siloxane transfer agents in flow reactors).…”

The Hiyama Cross‐Coupling Reaction at Parts Per Million Levels of Pd: In Situ Formation of Highly Active Spirosilicates in Glycol Solvents

“…[3] This drawback has limitedthe range of industrialappli-cations of the Hiyama coupling reaction. Althoughm any types of organosilicon reagents have been developed to permitt he Hiyamac oupling processes to proceed under milder conditions with wide functional-group tolerance, [4,5] the reduction of the catalystl oading to ppm levels remains ac hallenging researcho bjective. [6] In this context,t he development of efficient and general methods for the Hiyamac oupling reaction with ppm loadings of the relevant palladium catalysts is highly desired.…”