Scheme
3 Trials to determine the allowable range of
diaryliodonium salts.
a Reaction conditions:1a (0.20 mmol),2 (0.40 mmol), rongalite (0.80 mmol), Bu4NBr
(1.0 equiv), DMSO (2.0 mL), 90
°C, 3 h, under Ar.b Isolated yields based on 1a .c X = OTf. d X =
BF4.
Subsequently, the effects of substituents on the
CF3-alkene were examined (Scheme 4). Using
CF3-alkenes with alkyl (4a –4c ),
alkoxy (4d –4f ), and halogen
(4g –4i ) substituents on the aromatic ring, the
reaction was observed to proceed well, and the target products were
isolated in yields ranging from 60% to 85%. The reaction involved bothortho - and meta -substituted CF3-alkenes,
resulting in the excellent-yield products 4j and 4k ,
respectively. It was discovered that this reaction was also compatible
with electron-withdrawing moieties such -CF3, -Ac, and
-COOEt, which gave the corresponding products 4l –4nin yields of 59–64%. Furthermore, heteroatom groups, such as
trimethylsilyl (4o ), amine (4p ), -SMe (4q )
and -OH (4r ) moieties, were discovered to be suitable for this
reaction. Experiments using polycyclic aromatic hydrocarbons as
substituents established that products 4s –4w could be
obtained in good yields (65–82%). Also, this reaction worked well in
the presence of heterocycle-substituted substrates
(4x −4ab ), with yields of 52−76%. In order to
illustrate the usefulness of this reaction, the late-stage
functionalizations of the anti-inflammatory drugs ibuprofen andnaproxen were assessed. These reactions gave the target products4ac and 4ad in yields of 73% and 66%, respectively.
Scheme 4 Trials to determine the allowable range of
CF3-alkenes.
a Reaction conditions: 1 (0.20 mmol),2a (0.40 mmol), rongalite (0.80 mmol), Bu4NBr
(1.0 equiv), DMSO (2.0 mL), 90 °C, 3 h, under Ar.b Isolated yields based on 1 .
In addition to the late-stage functionalizations stated above, this
method was also carried out on a larger 5 mmol scale, yielding the
target product in a 66% isolated yield (Scheme 5).
Scheme 5. Gram-scale synthesis. a For
details, see the Supporting Information.
A number of control experiments were carried out to elucidate the
mechanism underlying this reductive cross-coupling reaction. No
significant formation of product 3a was observed in the case
that CF3-alkene 1a was reacted with
diaryliodonium salt 2a in the presence of TEMPO, indicating
that this transformation likely involves radicals (Scheme 6a). A
standard radical trapping experiment with 1,1-diphenylethylene was also
carried out and radical adduct 5 was identified by gas
chromatography-mass spectrometry while product 3a was obtained
in a 58% yield (Scheme 6b). In other trials, 1.0 equiv of
H2O was added to the reaction to trap any anions that
may have been generated and the un-defluorinated product 3a′was detected by gas chromatography-mass spectrometry, while product3a was separated in a 72% yield (Scheme 6c).
A plausible reaction mechanism is
showed in Scheme 6d based on the present control experiments and
previous work.[12] At the beginning, the pyrolysis
of rongalite generates SO22- and also
releases HCHO and H+. Subsequently, the
SO22- that is gradually released and
diaryliodonium salt 2 undergo a single electron transfer
process to produce aryl radical A . The reaction of this radical
and CF3-alkene 1 furnishes the radical
intermediate B . Finally, B is reduced by either a
sulfur dioxide anion or a sulfur dioxide radical anion to give anion
species C . The latter undergoes defluoridation to deliver the
desired gem -difluoroalkene product 3 . It is worth noting
that the chemoselective radical reduction in this reaction is vital to
realizing this transformation.
Scheme 6. Mechanistic
study.
Conclusions
In summary, a transition-metal-free allylic defluorination reductive
cross-coupling between CF3-alkenes and diaryliodonium
salts was established for the construction ofgem -difluoroalkenes. The industrial product rongalite was
employed as both a radical initiator and reductant. A catalyst was not
required and the use of the control-release rongalite instead of a metal
powder reducing agent promoted a sequential and highly selective
single-electron transfer process. Through this method, anti-inflammatory
drugs could be subjected to late-stage functionalization and a scaled-up
version of this synthesis was also achieved.
Experimental
All the materials and solvents were commercially available and used
without further purification. TLC analysis was performed using
pre-coated glass plates. Column chromatography was performed using
silica gel (200–300 mesh). 1H spectra were recorded
in CDCl3 and DMSO-d 6 on 600/400
MHz NMR spectrometers and resonances
(δ) are given in parts per million
relative to tetramethylsilane. Data are reported as follows: chemical
shift, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet,
h = quintet, p = sextet, m = multiplet), coupling constants (Hz) and
integration. 13C
spectra were recorded in
CDCl3 and DMSO-d 6 on 150/100 MHz
NMR spectrometers and resonances (δ) are given in ppm.19F spectra were recorded in CDCl3 and
DMSO-d 6 on 376 MHz NMR using TMS as internal
standard. High-resolution mass spectra (HRMS) were obtained by
electrospray ionization (ESI) on a TOF mass analyzer. The X-ray
crystal-structure determinations of 3ae were obtained on a
Bruker SMART APEX CCD system. Rongalite was commercially available (CAS
No: 149-44-0) and purchased from TCI corporation.