Development of Stereocontrolled Palladium(II)-Catalyzed Domino Heck/Suzuki β,α-Diarylation Reactions with Chelating Vinyl Ethers and Arylboronic Acids

Abstract

A stereoselective and 1,4-benzoquinone-mediated palladium(II)-catalyzed Heck/Suzuki domino reaction involving metal coordinating cyclic methylamino vinyl ethers and a number of electronically diverse arylboronic acids has been developed and studied. Diastereomeric ratios up to 39:1 and 78 % isolated yields were obtained. The stereoselectivity of the reaction was found to be highly dependent on the nature of the arylboronic acid and the amount of water present in the reaction mixture. Thus, a domino β,α-diarylation-reduction of chelating vinyl ethers can now be accomplished and stereochemically controlled, given that optimized conditions and an appropriate chiral auxiliary are used. To the best of our knowledge, this represents the first example of a stereoselective, oxidative Heck/Suzuki domino reaction in the literature.

Keywords: chirality; domino reactions; palladium; stereoselective catalysis; water effects.

Scheme 1

Simplified catalytic cycle for the domino oxidative Heck/Suzuki diarylation employing chiral chelating vinyl ethers.

Scheme 2

Reaction of 1 with different arylboronic acids 4 yielding domino product 5 and/or oxidative Heck product 8.

Figure 1

Influence of water content on the diastereoselectivity (d.r.: •) and yield (determined by NMR: ▪) of the chiral diphenylation of olefin 1 (see the Experimental Section for full details).

Scheme 3

A) Synthesis of (R)-1-methyl-3-(vinyloxy)piperidine 2 from (S)-(1-methylpyrrolidin-2-yl)methanol (>49:1 e.r.). B) Reaction of 2 with different arylboronic acids 4 yielding domino product 6 and/or oxidative Heck product 9. Reagents and conditions: a) Trifluoroacetic anhydride, Et₃N, dry THF, 0–20 °C; b) Aq NaOH (5 M), 55 %, >49:1 e.r.; c) Ethyl vinyl ether, 2,2′-bipyridine, Pd(O₂CCF₃)₂, O₂ (1 atm), 60 °C, 37 %, >49:1 e.r.; d) Pd(O₂CCF₃)₂, p-BQ, H₂O, 1,4-dioxane.

Figure 2

Influence of water content on the diastereoselectivity (d.r.: •) and yield (determined by NMR: ▪) of the chiral diphenylation of olefin 2 (see the Experimental Section for full details).

Scheme 4

Reaction between racemic trans-N,N-dimethyl-2-(vinyloxy)cyclohexanamine (rac-3) and phenylboronic acid 4 c. Reagents and conditions: a) vinyl ether rac-3 (1 equiv), 4 (4 equiv), p-BQ (1.5 equiv), Pd(O₂CCF₃)₂ (0.04 equiv), H₂O (10 equiv), 1,4-dioxane (1.5 mL), 40 °C, 40 %, 2:1 d.r. (see the Experimental Section for further details).

Figure 3

Crystals of (S,S)-11 were obtained by vapor diffusion crystallization. Thermal ellipsoids are drawn at the 50 % probability level and displays the preferred conformation (S,S)-11.