Allylation of C-, N-, and O-Nucleophiles via a Mechanochemically-Driven Tsuji-Trost Reaction Suitable for Late-Stage Modification of Bioactive Molecules

Abstract

We present the first solvent-free, mechanochemical protocol for a palladium-catalyzed Tsuji-Trost allylation. This approach features exceptionally low catalyst loadings (0.5 mol %), short reaction times (<90 min), and a simple setup, eliminating the need for air or moisture precautions, making the process highly efficient and environmentally benign. We introduce solid, nontoxic, and easy-to-handle allyl trimethylammonium salts as valuable alternative to volatile or hazardous reagents. Our approach enables the allylation of various O-, N-, and C-nucleophiles in yields up to 99 % even for structurally complex bioactive compounds, owing to its mild conditions and exceptional functional group tolerance.

Keywords: Ammonium Salts; Ball Milling; Green Chemistry; Mechanochemistry; Solvent Free.

Figure 1

Pd‐catalyzed mechanochemical reactions according to their first appearance in literature (top) and the mechanochemical Tsuji–Trost allylation (middle) with an outline of potential application in late‐stage functionalization of bioactive compounds (bottom).

Figure 2

Optimization of the reaction conditions for the mechanochemical Tsuji–Trost allylation. Reactions were performed on a 0.5 mmol scale under air in an IST636 mixer mill, using a Teflon milling jar (7 mL) and two ZrO₂ milling balls (one with 7 mm diameter, one with 10 mm diameter, see Supporting Information for details) at a frequency of 30 Hz. Allyl trimethylammonium chloride (II) was used as allylating agent and 4‐hydroxybiphenyl (I) as nucleophile, [Pd(allyl)Cl]₂ as catalyst (cat  1) and rac‐BINAP as ligand (L  1). Full table see SI. [a] Reaction performed in toluene (0.5 M) at 60 °C with a reaction time of 90 min.

Scheme 1

Scope of the Pd‐catalyzed, mechanochemical Tsuji–Trost reaction of O‐, N‐, and C‐nucleophiles. Reactions were performed on a 0.5 mmol scale under air in an IST636 mixer mill, using a Teflon milling jar (7 mL) and two ZrO₂ milling balls (one with 7 mm diameter, one with 10 mm diameter, see Supporting Information for details) with a milling time of 90 minutes at a frequency of 30 Hz. If not stated otherwise, K₂CO₃ was used as the base. Isolated yields are shown. [a] Reaction performed in toluene (0.5 M) at 60 °C with a reaction time of 90 min. [b] Reaction was performed on a 5.5 mmol scale using 2 Teflon milling jars (25 mL) each equipped with two 12.7 mm ZrO₂ milling balls. [c] Cs₂CO₃ was used as the base. [d] No base. [e] 2.5 equiv. of II. [f] 3 equiv. of the base were used. [g] 1 equiv. of II, 1 mol % Pd[(allyl)Cl]₂, 2 mol % rac‐BINAP.

Scheme 2

Scope of the Pd‐catalyzed, mechanochemical Tsuji–Trost reaction employing various substituted allyl trimethylammonium salts as allylating agents. Reactions were performed on a 0.5 mmol scale under air in an IST636 mixer mill, using a Teflon milling jar (7 mL) and two ZrO₂ milling balls (one with 7 mm diameter, one with 10 mm diameter, see Supporting Information for details) with a milling time of 90 minutes at a frequency of 30 Hz. If not stated otherwise, K₂CO₃ was used as the base. Isolated yields are shown. [a] 2 mol % of Pd[(allyl)Cl]₂ and 4 mol % rac‐BINAP were used. [b] Cs₂CO₃ was used as the base. [c] 3 equiv. of base were used.

Scheme 3

Enantioselective reaction towards (R) ‐ 43 using chiral (R)‐SEGPHOS ligand.