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