Stereospecific synthesis of unsymmetrical (E)- and (Z)-1,2-difluorostilbenes

• The stereospecific synthesis of unsymmetrical (E)-1,2-difluorostilbenes.
• The stereospecific synthesis of unsymmetrical (Z)-1,2-difluorostilbenes.
• One-pot synthesis of unsymmetrical 1,2-difluorostilbenes.
• Synthesis from readily obtainable starting materials: potential for scale up.
• 1,4-dioxane solvent system for increased rate of Suzuki reactions.

The synthesis of 1,2-difluorostilbenes via a Susuki reaction using a benzene/ethanol/water solvent mixture required long reaction times and generated significant quantities of a homo-coupled boronic acid product, which was difficult to separate. Therefore, we attempted 1,4-dioxane as a solvent for these reactions, which showed remarkable increased reaction rates and minimized the amount of homo-coupled products to aid in purification. Both (E)- and (Z)-1-chloro-1,2-difluorostyrenes stereospecifically gave the 1,2-difluorostilbenes in moderate to excellent yields. We investigated 4 protocols for the reaction. Protocols 2 and 3 were recommended for scale up, since the chlorostyrene starting material can be obtained in large quantities stereospecifically as described in previous reports. This work represents the first practical synthesis of unsymmetrical (E)- and (Z)-1,2-difluorostilbenes from readily available starting materials.

Figure optionsDownload as PowerPoint slideA methodology was developed for the synthesis and purification of unsymmetrical (E)- or (Z)-1,2-difluorostilbenes using 1,4-dioxane, which enhanced the reaction rate and minimized the amount of homo-coupled product. Several protocols were developed to accomplish this task. However, protocols starting from 1-chloro-1,2-difluorostyrenes was recommend for scaled up procedures. This methodology currently represents the most practical synthesis of either (E)- or (Z)-unsymmetrical 1,2-difluorostilbenes.