Microwave-Assisted Highly Regioselective Heck Type Vinylations of Vinyl Ethers

1. Microwave-Assisted Highly Regioselective Heck Type Vinylations of Vinyl Ethers Alexander Stadler, Henrik von Schenck, Karl S. A. Vallin, Mats Larhed and Anders Hallberg* Division of Org. Pharm. Chemistry, BMC, Uppsala University, Box 574, SE-75123 Uppsala, Sweden alexander.stadler@orgfarm.uu.se R = Me R = Et 45% R = Me R = Et 46% R = Me R = Et 28% R = Me R = Et 30% Chelating Vinyl Ether Ligand Pz DE [kcal/mol] PPh3 PPh3 PPh3 Product Yield* Product Yield* 49% 65% 51% 51% 47% 58% 60% 64% 1 15.1 2 10.7 4.1 3 Introduction Heck coupling reactions have been of current interest for the last four decades as they are powerful tools in organic and medicinal chemistry. Especially methods employing catalyst directing amino groups for control of regioselectivity with electron-rich vinyl ethers have been investigated in recent years. We describe herein a microwave-assisted protocol for regioselective terminal coupling of several alkenyl triflates towards chelating vinyl ethers (1-3). Using a dedicated monomode microwave instrument (Smith Synthesizer, Personal Chemistry), reaction times for these exclusive terminal vinylations could be reduced to 10-30 minutes instead of 24-48 h. The corresponding dienes were obtained in moderate to good yields after simple workup including extraction and flash column chromatography. Results Experimental:The microwave protocol employed Pd(OAc)2/PPh3 as the precatalytic system to obtain the desired dienes in an average 4:1 trans/cis ratio. Similar yields but decreased trans/cis ratio could be achieved by only 10 min heating at 160 C. Whereas the regioselectivity was excellent (99:1 terminal coupling) for the dimethyl- and the pyrrolidone-derivatives, the diethylamino olefin showed lower selectivity (92:8). This trend illustrates the effect of the different properties of the palladium(II) coordinating amino groups for the outcome of the reaction. Further, the higher yields may be a consequence of decreased coordination strengths of the diethyl derivative. DFT calculations:Density functional theory (B3LYP/6-311G(d,p)) was employed to calculate the coordination strength (DE) of the nitrogen auxiliary in a set of cationic vinylpalladium(II) complexes modeling the experimental systems.The strong coordination of the pyrrolidone (1) fits nicely with the low yielding experiments indicating trapping of palladium in a stable chelating p-complex. The relatively weak N-Pd coordination of diethyl-aminoethyl vinyl ether (3) correlates with the decreased regioselectivity observed. The intermediate coordination strength of dimethyl-aminoethyl vinyl ether (2) provides the optimal balance to achieve both, good yields and high regioselectivity. Microwave-mediated Heck Couplings (0.5 mmol scale):† Chelating Complex Formation: †1mL DMSO, 1 mol% Pd(OAc)2, 3 mol% PPh3, 120 C, 30 min *Isolated yields after flash chromatography (>95% pure) Conclusions • Efficient MW-mediated terminal vinylations utilizing electron-rich vinyl ethers • Raising temperature reduces reaction time to 10 min • Reaction progress explained by coordination strength • of nitrogen auxiliary • Experimental results confirmed by computational • calculations • Best results with the dimethylaminoethyl vinyl ether (2) • Trapping of the dienes by subsequent Diels-Alder • reaction under further investigation.