Palladium-catalyzed phosphonyldifluoromethylation of alkenes with bromodifluoromethylphosphonate†

Efficient and straightforward methods for the synthesis of fluorinated compounds are increasingly important in the discovery of new biologically active molecules and advanced functional materials. Over the past few years, considerable efforts have been made in the fluoroalkylation of arenes, however efficient strategies for the synthesis of alkenes bearing fluorinated functional groups are less studied. Very recently, we developed an efficient and straightforward method for the preparation of fluoroalkylated alkenes through palladium-catalyzed Heck-type reaction of fluoroalkyl halides. However, the reaction of bromodifluoromethylphosphonate (BrCF2PO(OEt)2) 1a via such a strategy remains a synthetic challenge because of the significant hydrodebromination of 1a. In this study, we describe the discovery and development of the reaction that meet this challenge. On the other hand, organic molecules containing the CF2PO(OR)2 group constitute a distinct class of fluorinated compounds due to their important applications in medicinal chemistry. For instance, difluoromethylphosphonates in which the hydrolysable P–O bonds are replaced by a stable P– CF2 bond are the best mimics of the phosphonate esters, thus providing a useful tool for the drug discovery and development. Conceptually, incorporation of CF2PO(OR)2 into alkenes could lead to the development of interesting molecules in life sciences because of the unique properties of the CF2PO(OR)2 group and the versatile synthetic utility of the carbonvcarbon double bond. Unfortunately, efficient methods to access phosphonyldifluoromethylated alkenes are very limited. Previously, such a structural motif can be prepared through copper catalyzed cross-coupling between [(di-ethoxyphosphinyl)difluoromethyl]zinc bromides and alkenyl halides. However, the requirement of multi-steps to prepare alkenyl halides and the use of the shelf-unstable difluoroalkylated zinc reagent restrict its wide-spread synthetic applications. The radical addition of alkynes with a phosphonyldifluoromethyl radical is an alternative strategy to produce phosphonyldifluoromethylated alkenes. But a Z/E mixture was obtained. Therefore, it is of great interest to develop a new and straightforward method to prepare such a valuable structural motif. We began this study by choosing diethyl (bromodifluoromethyl)phosphonate 1a and styrene 2a as model substrates Xingang Zhang Xingang Zhang is a research professor in the Shanghai Institute of Organic Chemistry (SIOC), Chinese Academy of Sciences (CAS). He graduated in 1998 from Sichuan University and received a Ph.D. in 2003 at SIOC, CAS. After his postdoctoral work at the University of Illinois at Urbana Champaign (UIUC), he joined the faculty of SIOC as a research associate professor in 2008, and became a research professor in 2012. His current research interests are focused on organofluorine chemistry. He received the Thieme Chemistry Journal Award 2014, the National Science Fund for Distinguished Young Scholars 2014, the Fifth Chinese Chemical Society-Royal Society of Chemistry Award for Outstanding Young Chemist (2015), and the 2015 RSC Fluorine Chemistry Prize. †Electronic supplementary information (ESI) available. See DOI: 10.1039/ c6qo00005c Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032, China. E-mail: [email protected]; Fax: (+86)-21-6416-6128; Tel: (+86)-21-5492-5333