Model Guided Development of a Simple Catalytic Method for the Synthesis of Unsymmetrical Stilbenes by Sequential Heck Reactions of Aryl Bromides with Ethylene

Abstract

Stilbenes are important and useful structural moieties, but methods for their preparation typically possess numerous inefficiencies. Presented here is a methodology for the two‐step, one pot preparation of unsymmetrical stilbenes via sequential Heck reactions. The first Heck reaction with ethylene gas was analysed as a function of temperature and pressure for electronically differentiated naphthyl bromides and model‐aided reaction optimization was utilized to define the system. In addition, reactNMR was utilized to determine ethylene solubility in common organic solvents useful for Heck reactions. Finally, an optimized sequential Heck reaction process was developed and applied to a range of substrates allowing for efficient preparation of unsymmetrical stilbenes, including the natural antioxidant, pterostilbene.magnified image

The Initiation Reaction of Hoveyda–Grubbs Complexes with Ethene

“…The maximum concentration of ethene in toluene under an ethene atmosphere was found to be c (ethene) = 0.093 mol·L –1 (at 303 K). This value is very close to that determined by 1 H NMR for a saturated solution of ethene in benzene-d 6 c (ethene) = 0.089 mol·L –1 (at 296 K) and in toluene …”

“…This value is very close to that determined by 1 H NMR for a saturated solution of ethene in benzene-d 6 c(ethene) = 0.089 mol•L −1 (at 296 K) 10b and in toluene. 36 The initiation of three different Hoveyda−Grubbs complexes (Schemes 1) with ethene was studied in the concentration range c(ethene)= 0.009−0.093 mol•L −1 . Since ethene is a gas under standard conditions with limited solubility in organic solvents, the available concentration range for initiation experiments is also limited.…”

Asymmetric Synthesis of a 5,6,7,8-Tetrahydro-1,6-naphthyridine Scaffold Leading to Potent Retinoid-Related Orphan Receptor γt Inverse Agonist TAK-828F

“…As the trifluoroborate was glass-corrosive, not atom-economical, and an expensive vinyl source, its replacement with ethylene gas was attempted. Although the Heck reactions using ethylene gas had been reported for an aryl chloride 14 and aryl bromides, 15 no example was available for the conversion of chloropyridines. Nonetheless, we launched high-throughput screening ( Table 1 ) 16 and successfully identified a new and effective set of conditions for the vinylation of 23 using DPEphos as the ligand ( Scheme 4 , method B).…”

Synthesis of Hydroxylated Stilbenes in a Batch and Flow Reactor: An Overview

“…This approach highlights another major advantage of flow chemistry, namely the ability to avoid time‐consuming and often unnecessary isolation procedures while achieving acceptable yields of 60–80 %. Apart from this, isolations are often difficult and dangerous, also because many intermediates are reactive or toxic, so an immediate second reaction is highly preferred for very sensitive styrenes prone to polymerisation [100] . Hydroxylated stilbenes and stilbenes in general can be used not only as a valuable product, but also as a good starting material for the synthesis of useful intermediates such as epoxides, which are often used in the production of various important chemicals.…”