1501969-19-2

Upstream product

• 86-81-7 3,4,5-trimethoxy-benzaldehyde 
• 87189-16-0 potassium 2-bromo-2,2-difluoroacetate 
• 1895-39-2 sodium chlorodifluoroacetate 

Downstream Products

• 1620095-90-0 1,2,3-trimethoxy-5-(2,2,2-trifluoroethyl)benzene 
• 1501969-11-4 5,5'-((2RS,3SR)-1,1,1,4,4,4-hexafluorobutane-2,3-diyl)bis(1,2,3-trimethoxybenzene) 

Relevant academic research and scientific papers

Acid-Catalyzed Hydrothiolation of gem-Difluorostyrenes to Access α,α-Difluoroalkylthioethers

The substitution of hydrogen atoms with fluorine in bioactive molecules can greatly impact physicochemical, pharmacokinetic, and pharmacodynamic properties. However, current synthetic methods cannot readily access many fluorinated motifs, which impedes utilization of these groups. Thus, the development of new methods to introduce fluorinated functional groups is critical for developing the next generation of biological probes and therapeutic agents. The synthesis of one such substructure, the α,α-difluoroalkylthioether, typically requires specialized conditions that necessitate early-stage installation. A late-stage and convergent approach to access α,α-difluoroalkylthioethers could involve nucleophilic addition of thiols across gem-difluorostyrenes. Unfortunately, under basic conditions, nucleophilic addition to gem-difluorostyrenes generates an anionic intermediate that can undergo facile elimination of fluoride to generate α-fluorovinylthioethers. To overcome this decomposition, we herein exploit an acid-based catalyst system to facilitate simultaneous nucleophilic addition and protonation of the unstable intermediate. Ultimately, the optimized mild conditions afford the desired α,α-difluoroalkylthioethers in high selectivity and moderate to excellent yields. These α,α-difluoroalkylthioethers are less nucleophilic and more oxidatively stable relative to nonfluorinated thioethers, suggesting the potential application of this unexplored functional group in biological probes and therapeutic agents.

Autocatalytic Synthesis of Thioesters via Thiocarbonylation of gem-Difluoroalkenes

Herein, we report a new method for the synthesis of acyethanethioates via thiocarbonylation of gem-difluoroalkenes with thiols. This reaction provides a new pathway to prepare thioesters under mild conditions without the use of any additives. Mechanistic

Organocatalytic strategy for hydrophenolation of gem-difluoroalkenes

Gem-difluoroalkenes are an easily accessed fluorinated functional group, and a useful intermediate for elaborating into more complex fluorinated compounds. Currently, most functionalization reactions of gem-difluoroalkenes, with or without a transition metal-based catalyst system, involve the addition or removal of a fluorine atom to generate trifluorinated or monofluorinated products, respectively. In contrast, we present a complementary “fluorine-retentive” reaction that exploits an organocatalytic strategy to add phenols across gem-difluoroalkenes to deliver β,β-difluorophenethyl arylethers. The products are produced in good to moderate yields and selectivities, thus providing a range of compounds that are underrepresented in the synthetic and medicinal chemistry literature.

Pd-Catalyzed Selective Carbonylation of gem-Difluoroalkenes: A Practical Synthesis of Difluoromethylated Esters

The first catalyst for the alkoxycarbonylation of gem-difluoroalkenes is described. This novel catalytic transformation proceeds in the presence of Pd(acac)2/1,2-bis((di-tert-butylphosphan-yl)methyl)benzene (btbpx) (L4) and allows for an efficient and straightforward access to a range of difluoromethylated esters in high yields and regioselectivities. The synthetic utility of the protocol is showcased in the practical synthesis of a Cyclandelate analogue using this methodology as the key step.

Photoredox-Coupled F-Nucleophilic Addition: Allylation of gem-Difluoroalkenes

A novel strategy for the expedient construction of CF3-embeded tertiary/quarternary carbon centers was developed by taking advantage of photoredox catalysis. Thanks to a key step of single-electron oxidation, electron-rich gem-difluoroalkenes, which otherwise are essentially reluctant towards F-nucleoplilic addition, now readily participate in this fluoroallylation reaction. Furthermore, this strategy provides an elegant example for the generation, as well as functionalization, of α-CF3-substituted benzylic radical intermediates using cheap and readily available starting materials.

Manganese-catalyzed synthesis of monofluoroalkenes: Via C-H activation and C-F cleavage

The manganese-catalyzed α-fluoroalkenylation of arenes via C-H activation and C-F cleavage has been described. This protocol provides a very useful method for the synthesis of monofluoroalkenes with predominant unconventional E-isomer selectivity which complements the existing strategies for the access to these molecular architectures. In addition, the selectivity of β-defluorination in the catalytic cycle not only determines the configurations of the products but also obviates the use of external oxidants, providing a good example in the exploitation of manganese-catalyzed redox-neutral C-H transformations.

Base Catalysis Enables Access to α,α-Difluoroalkylthioethers

A nucleophilic addition reaction of aryl thiols to readily available β,β-difluorostyrenes provides α,α-difluoroalkylthioethers. The reaction proceeds through an unstable anionic intermediate, prone to eliminate fluoride and generate α-fluorovinylthioethers. However, the use of base catalysis overcomes the facile β-fluoride elimination, generating α,α-difluoroalkylthioethers in excellent yields and selectivities.

Metal-free trifluoromethylation of aromatic and heteroaromatic aldehydes and ketones

The ability to convert simple and common substrates into fluoroalkyl derivatives under mild conditions remains an important goal for medicinal and agricultural chemists. One representative example of a desirable transformation involves the conversion of aromatic and heteroaromatic ketones and aldehydes into aryl and heteroaryl β,β,β-trifluoroethylarenes and -heteroarenes. The traditional approach for this net transformation involves stoichiometric metals and/or multistep reaction sequences that consume excessive time, material, and labor resources while providing low yields of products. To complement these traditional strategies, we report a one-pot metal-free decarboxylative procedure for accessing β,β,β- trifluoroethylarenes and -heteroarenes from readily available ketones and aldehydes. This method features several benefits, including ease of operation, readily available reagents, mild reaction conditions, high functional-group compatibility, and scalability.