Background and Originality Content
Fluorine-containing moieties can give novel biological functions while also enhancing lipophilicity and metabolic stability in organic compounds.[1] Among the numerous possible fluorine-containing compounds,gem -difluoroalkenes have been identified as a unique class of polyfluorinated substances having electronic and spatial distributions that are strikingly similar to those of carbonyl groups.[2] As a result, the addition of fluorine-based functional groups to various molecules could have potential applications in the field of biomedicine.[3]
A variety of protocols for the synthesis of gem -difluoroalkenes based on the allylic defluorination of CF3-alkenes have been developed throughout the last decade.[4-7]Among them, reductive cross-coupling strategy, as an important method for cross-linking of different electrophilic reagents, plays a pivotal role in the construction of gem -difluoroalkenes (Scheme 2A). One of the most classic types is the reaction system using transition metal catalysts and metal reductants, which has been well developed through the use of different electrophilic reagents (eg. Alkyl halides, Katritzky salts, NHPI esters, etc) and catalysts (eg. Ni, Ti, Cr, Fe, Co, etc).[8] Afterward, new methods under photoredox-catalyzed conditions alongScheme 1 Representative pharmaceuticals containing the gem -difluoroalkene moiety.
with organic reducing agent (eg. Silanol, Amine, Hantzsch ester, etc) have been developed, a series of gem -difluoroalkenes can be synthesized.[9] More recently, electrochemical reactions come into their own. In this type of reaction, it is no longer necessary to add additional reductants, instead, the electrochemical environment itself can provide sufficient electrons for the reductive cross-coupling reaction.[10] Although these three reductive cross-coupling strategies described above have been established in many works. Some reactions still unavoidably used transition metal catalysts or stoichiometric metal reductants, which would result in negative impacts to the environment. Furthermore, some complex reaction conditions with expensive equipment undoubtedly result in much higher costs. Therefore, developing novel, concise and cost-effective reductive cross-coupling synthesis methods forgem -difluoroalkenes would be of great interest in synthetic methodology.
Scheme 2 Background and synopsis of the current work.
A recent work by Jiang et al. using formate as an inexpensive single-electron donor to mediate reductive cross-couplings for the construction of alkyl-alkyl sulfones has come to our attention owing to its green and simple conditions (Scheme 2B).[11] Inspired by this work, we were interested in exploring a potentially suitable reducing salt to mediate the allylic defluorination reductive cross-coupling, as it could offer significant synthetic utility despite being rarely reported. On this basis, the present work demonstrates a transition-metal-free allylic defluorination reductive cross-coupling between CF3-alkenes and diaryliodonium salts mediated by rongalite (Scheme 2C). Notably, this reaction is easy to operate, and the cheap and easily available industrial product rongalite acts as both free radical initiator and reducing agent, avoiding the use of catalysts, metal reducing agents and complex apparatus. As it also provides a new illustration of the allylic defluorination reductive cross-coupling paradigm.
Results and Discussion
To optimize this process, the CF3-alkene 1a and diphenyliodonium trifluoromethanesulfonate 2a were utilized as model substrates (Table 1). Product 3a was generated in a 13% yield from a reaction involving 1a , 2a (2 equiv) and 2 equiv of rongalite performed in N , N -dimethylformamide at 80 °C for 3 hours under argon (entry 1). Subsequent studies with several solvents found that dimethyl sulfoxide offered the best yield (entries 2–5). The impact of rongalite concentration was also investigated, and 4.0 equiv was discovered to be the ideal quantity (entries 6–8). The reaction was suppressed when the temperature was brought down to 70 °C, whereas it was promoted when the temperature was brought up to 90 °C. However, further increases in temperature had a limited effect (entries 9–11). A number of phase transfer reagents were assessed and were all found to promote the reaction, with tetrabutylammonium bromide producing the best result (entries 12–14). The use of diphenyliodonium tetrafluoroborate 2a’ instead of 2a in conjunction with 1a did not change the yield significantly (entry 15). Finally, this process was conducted without rongalite and none of the target product was obtained (entry 16).
Table 1 . Optimization of the Reaction Conditionsa,b