Decarboxylative and dehydrative coupling of dienoic acids and pentadienyl alcohols to form 1,3,6,8-tetraenes

Dienoic acids and pentadienyl alcohols are coupled in a decarboxylative and dehydrative manner at ambient temperature using Pd(0) catalysis to generate 1,3,6,8-tetraenes. Contrary to related decarboxylative coupling reactions, an anion-stabilizing group is not required adjacent to the carboxyl group. Of mechanistic importance, it appears that both the diene of the acid and the diene of the alcohol are required for this reaction. To further understand this reaction, substitutions at every unique position of both coupling partners was examined and two potential mechanisms are presented.


Kinetic data for different phosphine ligands
To a prepared solution of Pd 2 dba 3 ·CHCl 3 (5 mol %) and designated ligand (see above and Chart; 20 mol %) in CDCl 3 (0.1 M) was added pentadienyl dienoate 9 (20 mg, 0.072 mmol) at ambient temperature. 1 H NMR spectra were obtained upon dissolution of the reagents and subsequent 1 H NMR spectra were obtained every 90 minutes. The formation of the product 10 was monitored and plotted versus time in Chart S1.

S22
Methyl cyclohexa-1,3-diene-1-carboxylate (S13) Following a previously reported procedure, ester S13 x was synthesized as a colorless oil, (350 mg, 30%). R f = 0.38 (75:25, hexanes/EtOAc). 1 H and 13 C NMR are consistent with literature reports. x This compound was prone to air oxidation to methyl benzoate so it was moved forward synthetically prior to complete removal of the solvent.

1,3-Cyclohexadiene-1-methanol (S14)
DIBAL-H in toluene (1.2 M, 4.1 mL, 5.0 mmol) was added to ester S13 (350 mg, 2.5 mmol) in THF (10 mL) at −78 °C. The reaction was allowed to warm to room temperature and stirred overnight. The reaction mixture was filtered through Celite ® , acidified with 10% aqueous HCl, extracted with diethyl ether, and dried using Na 2 SO 4 . The solution was concentrated and purified via silica gel chromatography (80:20, hexanes/EtOAc) to give (197 mg, 72%) of alcohol S14. R f = 0.19 (80:20, hexanes/EtOAc). 1 H and 13 C NMR are consistent with literature reports. xi This compound was prone to air oxidation to benzyl alcohol so it was moved forward synthetically prior to complete removal of solvent. The impurities were taken into account when determining the yield of S14.

S28
(2-Vinylcyclopent-1-en-1-yl)methyl acetate (7d) To a solution of alcohol S15 (20 mg, 0.16 mmol) and triethylamine (45µL, 0.32 mmol) in CH 2 Cl 2 (1.6 mL) was added acetic anhydride (19 µL, 0.19 mmol) and DMAP (2.0 mg, 0.016 mmol) at 0 °C. After stirring for an hour at room temperature, the reaction was diluted with diethyl ether and washed with water. The aqueous layer was back extracted with diethyl ether, and the combined organic layers dried using Na 2 SO 4 and concentrated. Purification via silica gel chromatography ( To a microwave vial was added diene 9 (40 mg, 0.14 mmol) xii and water (2.7 µL, 0.15 mmol) in CH 2 Cl 2 (2 mL). Tetrakis-(triphenylphosphine) palladium (16 mg, 0.014 mmol) was added and the vial was sealed and purged with N 2 . The mixture was a bright orange color. After 24 hours at room temperature, the mixture was a turbid yellow color. The reaction was concentrated and purified via silica gel chromatography (97:3, hexanes/EtOAc) to yield tetraene 10 (22 mg, 76%) as a yellow oil. Scale-up beyond 100 mg resulted in decreased yields; however, when eight vials were run simultaneously and purified together, the yield remained around 70%. R f = 0.90 (90:10, hexanes/EtOAc). Spectral data matched those previously reported. xii Dienoate 11 (40 mg, 0.17 mmol) xii was added to a small vial with CH 2 Cl 2 (2 mL) after which tetrakis-(triphenylphosphine) palladium (19.7 mg, 0.017 mmol) was added. The vial was sealed and purged with N 2 . When initially prepared, the solution was a dark orange color, but after 24 hours, it was a light yellow color. At this time, the reaction was concentrated and purified via silica gel chromatography (hexanes) to yield ethyl tetraene 12. The yield was inconsistent due to the extreme volatility of the product which made removing solvent difficult. xii

Experimental procedures for two component decarboxylative coupling
General Procedure: A microwave vial with dienoic acid 5 (1.0 equiv), pentadienyl substrate 6 (1.2 equiv) and water (1.1 equiv) in CDCl 3 (0.1 M) was capped with a septum, and purged with N 2 . Tris(dibenzylideneacetone)dipalladium(0)-chloroform adduct (5 mol %) and PPh 3 (20%) were dissolved in CDCl 3 (0.1 mL) and added to the mixture. The mixture was left at room temperature under a balloon of N 2 for 48 hours. The solution was concentrated and purified via silica gel chromatography using pentane.

Product inhibition experiment
Two reactions were run side-by-side to determine if the 1,3,6,8-tetraenes were inhibiting formation of product (see below). The reactions used the same starting dienoic acid, divinylcarbinol, catalyst, ligand, solvent, temperature, and concentration. The only difference was that one reaction had 30 mol % of a previously synthesized tetraene product. In the presence of the tetraene, the yield dropped from 35% to 21% for the side-by-side comparison.

Computational methods
Computed energies, optimized molecular geometries, and harmonic frequencies were calculated with the Gaussian 09 program. xiii Two levels of theory were utilized for the structures reported in Scheme 3. For the Baylis-Hillman type mechanism, a 6-311+G** basis was used in order to accommodate the large degree of charge separation in the structures. For the new mechanism we proposed, the more modest 6-31G* basis was employed. The hybrid B3LYP functional was utilized along with a 6-31G* basis and a PCM approximation of water solvation. The nudged elastic band (NEB) method xiv was used to map out reaction pathways and locate transition states. NEB is a computational algorithm for determining the reaction energy path (REP) between a reactant and product. A series of interpolated structures, or images, is generated to depict the geometric evolution between the two end points, and the corresponding energies and energy gradients are computed for each image. The total gradient, or force, on each image, is projected into so-called parallel and perpendicular forces, where the former refers to the force along the REP, while the latter is that normal to the REP. Force constants are applied along the parallel direction to prevent the images from collapsing back to the local minima (the reactant or product) and to keep the images evenly spaced. The perpendicular forces are minimized (in mass weighted coordinates with our implementation, to accelerate convergence, which is particularly useful for systems with heavy atoms). In cases where more than one pathway exists between endpoints, NEB distinguishes between the paths and is able to locate the one of lowest energy. While NEB can be run to convergence to obtain the transition state, in practice for this study only a few hundred NEB cycles were run, the last one hundred or so with the climbing image option activated to ensure that the highest of the movable images was as close to the transition state as possible. This image, along with additional data from the NEB calculation, was utilized

S50
in the Modified Dimer program xv to locate the transition state. Dimer is a local surface-walking algorithm that calculates only the lowest eigenvalue and eigenvector, rather than the full Hessian. The dimer vector, in our case, is defined by the two NEB images (the estimate of the TS and an adjacent image or point defining the tangent vector) and is rotated to locate the lowest curvature mode. The algorithm then steps in this direction uphill toward the saddle point. Table S1. Cartesian coordinates and DFT/B3LYP/6-311+G** or 6-31G* energies of optimized molecular structures from Scheme 3. The first line of each list of coordinates is the number of atoms, the second line is the title line and total energy (in Hartrees), and the rest are the coordinates (units in Ångstroms