Organic Letters
Letter
this series the pyridine derivative (3u) was also obtained in
52% yield. On the other hand, 1,1-diphenylethylene derivatives
proved to be less reactive in this transformation. Therefore,
increased catalyst and base loadings were necessary to
accomplish the desired coupling. We managed to synthesize
the 3v and 3w derivatives in 55% and 58% yields, respectively.
Next, we broadened the scope of the photocatalytic
fluoroalkylation method with versatile fluoroalkyl iodides
(Scheme 3). We found that 1,1-difluoro-2-iodoethane is also
capable of participating in the coupling reaction.
with difluorocarbene sources,16 and direct difluoroethylation of
terminal alkene is unprecedented.
Applying the previously used reaction conditions, we found
that the coupling of 1,1-difluoro-2-iodoethane with styrene
requires a 24 h reaction time to reach completion, and we
could isolate the corresponding difluoroethylated styrene
product (5a) in 82% yield. With the slightly modified
procedure, 12 additional derivatives were prepared to explore
the scope of the photocatalyzed coupling reaction. This
transformation also possesses good functional group tolerance,
and alkyl (5b, 5c, 5d), aryl (5e), halogen (5f−k), ester (5l),
methoxy (5m, 5n), and aldehyde (5o) derivatives were
successfully synthesized.
a
Scheme 3. Scope of Different Fluoroalkyl Iodides
Increasing further the versatility of the fluoroalkyl part we
utilized 1H,1H-pentafluoropropyl iodide as a coupling partner,
and we obtained the corresponding coupling products under
the standard reaction conditions. In this case the pentafluor-
opropylated derivatives (5p−t) were isolated in 46−62% yield.
Additionally, two other fluoralkyl iodides were also tested in
this transformation, 1,1,2,2-tetrafluoro-3-iodopropane and
1H,1H,5H-octafluoropentyl iodide, and successfully gave the
desired coupled products (5u, 5v) in 68% and 53% yield,
respectively, which demonstrates that longer fluorous chains
are also applicable in this palladium-catalyzed photochemical
transformation.
Results of the radical quenching and light on−off experi-
ments17 support that the fluoroalkylation reaction follows the
general mechanism of the palladium-catalyzed alkylations.14
The Xantphos−Pd(0) complex can be excited with blue light
(440−460 nm), and then this Pd species reacts with fluoroalkyl
iodide in the SET reaction, supposedly generating a
Xantphos−Pd(I)−I and fluoroalkyl radical pair (the latter
was trapped with TEMPO to prove its presence),17 which are
in close proximity. Alkene reacts with this palladium(I)
intermediate through insertion or radical addition, and then
a β-hydrogen radical elimination could form the coupled
styrene product and the common H−Pd(II)−I. This latter
species undergoes base-assisted reductive elimination to
produce Xantphos−Pd(0), ready for the next catalytic cycle.
In conclusion we developed a visible light driven palladium-
catalyzed Heck-type coupling between styrenes and fluoroalkyl
iodides at room temperature, which enables the introduction of
versatile fluoroalkyl chains into terminal alkene functionality. A
series of styrene derivatives were subjected to the present
reaction conditions and formed the corresponding fluoroalkyl
derivatives in good yields. In our synthetic studies five different
fluoroalkyl iodides were successfully utilized. This method
offers an efficient disconnection to incorporate fluorine-
containing functional groups into styrene derivatives, which
could serve as a useful derivatization method to obtain
fluoroalkenylated compounds.
a
Standard reaction conditions: substrate (0.5 mmol), fluoroalkyl
iodide (1.5 equiv), Cs2CO3 (1.5 equiv), Pd(OAc)2 (5 mol %),
Xantphos (10 mol %) was used in 2.5 mL degassed benzene under Ar
atmosphere, irradiated with single 10 W 440−445 nm LEDs at 25 °C.
b
Average of two reactions.
ASSOCIATED CONTENT
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* Supporting Information
The Supporting Information is available free of charge at
This attracted our interest because the difluoromethyl
moiety is a well-studied motif in medicinal chemistry. The
difluoromethyl group is isosteric and isopolar with the −OH
and −SH groups and can behave as a H-donor as well.15 The
preparation of difluoroethylated styrene derivatives is per-
formed only through the functionalization of allylic halides
General information, synthesis procedures, character-
izations of products (1H, 13C, 19F NMR, IR, HRMS),
C
Org. Lett. XXXX, XXX, XXX−XXX