Synthesis of Polyflourinated Biphenyls; Pushing the Boundaries of Suzuki-Miyaura Cross Coupling with Electron-Poor Substrates

Article abstract of DOI:10.1021/acs.joc.7b02267

Polyfluorinated biphenyls are interesting and promising substrates for many different applications. Unfortunately, all current methods for the syntheses of these compounds only work for a hand full of molecules or only in very special cases. Thus, many of these compounds are still inaccessible to date. Here we report a general strategy for the synthesis of a wide range of highly fluorinated biphenyls. In our studies we investigated crucial parameters, such as different phosphine ligands and the influence of various nucleophiles and electrophiles with different degrees of fluorination. These results extend the scope of the already very versatile Suzuki-Miyaura reaction toward the synthesis of very electron-poor products, making these more readily accessible. The presented methodology is scalable and versatile without the need for elaborate phosphine ligands or Pd-precatalysts.

Full text of DOI:10.1021/acs.joc.7b02267

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Article
Synthesis of Polyflourinated Biphenyls. Pushing the Boundaries
of Suzuki-Miyaura Cross Coupling with Electron-Poor Substrates.
David Bulfield, and Stefan M. Huber
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b02267 • Publication Date (Web): 21 Nov 2017
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Synthesis of Polyflourinated Biphenyls. Pushing the Boundaries of Su-
zuki-Miyaura Cross Coupling with Electron-Poor Substrates.
David Bulfield* and Stefan M. Huber*
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Fakultät fü r Chemie und Biochemie, Ruhr-Universität Bochum, Universitätsstraße 150, 44801 Bochum, Germany
ABSTRACT: Polyfluorinated biphenyls are interesting and promising substrates for many different applications. Unfortu-
nately, all current methods for the syntheses of these compounds only work for a hand full of molecules or only in very
special cases. Thus, many of these compounds are still inaccessible to date. Here we report a general strategy for the syn-
thesis of a wide range of highly fluorinated biphenyls. In our studies we investigated crucial parameters such as different
phosphine ligands and the influence of various nucleophiles and electrophiles with different degrees of fluorination. These
results extend the scope of the already very versatile Suzuki-Miyaura reaction towards the synthesis of very electron-poor
products, making these more readily accessible. The presented methodology is scalable and versatile without the need for
elaborate
phosphine
ligands
or
Pd-precatalysts.
symmetric compounds, or systems involving strong elec-
tron withdrawing substituents such as CF3 or nitro groups
that serve as directing group.17 Additionally, acidic protons
can cause problems due to the requirement of basic
metalorganic reagents, such as lithium or zinc organyls.
Also the formation of arynes following M-F elimination has
to be taken into consideration in highly fluorinated aro-
matic systems. Both issues can result in the formation of
complex product mixtures and need to be addressed in the
design of the syntheses.
Introduction
Fluorinated biphenyls and their derivatives are interesting
building blocks for many different applications because of
their electron-poor nature, intrinsic rigidity and chemical
stability. One example is the development of liquid crystal-
line materials, which are important for liquid crystal dis-
plays (LCDs).1-3 Perfluorinated biphenyls have also been
considered for the development of organic light emitting
diodes (OLEDs)4 and organic semiconductors5, making use
of their electronic properties. Particularly, but not exclu-
sively, the rigidity of these compounds is interesting for
Besides nucleophilic substitution, different metal mediated
reactions have been used for the synthesis of fluorinated
biaryl compounds. One approach by T. Suzuki and cowork-
ers was to use Ullmann couplings during their synthesis of
perfluorinated oligo(p-phenylene)s.18 The most prominent
synthetic methods for building up biaryl structures are
without doubt the Negishi19, Suzuki-Miyaura20-21 and Stille
coupling22. Concerning the latter, examples of couplings
containing fluorinated aryl compounds are very rare and
most examples refer to substrates which are only fluori-
nated on the electrophilic side.23-28 To our knowledge only
one example is known in which two aryl sp2 carbons are
coupled to each other.29 Nevertheless the Stille coupling
with fluorinated stannane derivatives is also known.30 In
the case of Negishi couplings also only few examples are
known and the fluorinated products only contain one or
two fluorine atoms.31-33 In contrast, more examples can be
found for the Suzuki-Miyaura coupling. The first goes back
applications in crystal engineering6-7
,
metal-organic
frameworks (MOFs)8, polymers of intrinsic microporosity
(PIMs)9-10, organic polymers of intrinsic microporosity
(OMIMs)11 and supramolecular chemistry12. In our group
different polyfluorinated polyphenyl compounds have
served as scaffold for halogen bond donors to build up
structures for molecular recognition13 and halogen bond
mediated catalysis14. In these studies, the fluorine substit-
uents play an important role since they ensure strong
halogen bonds due to the electron withdrawing nature of
the fluorine atoms.
The synthesis of highly fluorinated polyphenyl compounds
is challenging since there are only few methods to synthe-
size these structures. The standard way is to synthesize
them by nucleophilic substitution.15-16 However, this meth-
od has the major drawback that it is only applicable to
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Previous Work
to M. Hird and coworkers in 1999, in which they synthe-
Pd(PPh3)4
K2CO3
HO
HO
1
2
3
4
5
6
7
8
sized fluorinated terphenyls as part of liquid crystals. The-
se contained up to four fluorine atoms, distributed to both,
the electrophilic and nucleophilic side of the cross-
coupling reaction.34 And although this is the first known
example in that respect, it is till date one of only a few
where both coupling partners are fluorinated. Much more
research has been conducted on compounds where only
one side of the biaryl is fluorinated. For example, Langer
and coworkers have shown that selective monoarylation of
fluorinated dibromobenzenes is possible.35-37 Also, M.
Schlosser and C. Heiss have shown that polyfluorinated
brominated compounds are suitable electrophiles in the
Suzuki-Miyaura coupling.38 For the coupling of mono-, di-
and trifluorinated boronic acids to non-fluorinated elec-
trophiles, different palladium catalysts have been found to
be active. 34, 39-46 Much less examples are found with higher
fluorinated compounds. For instance, in the case of tetra-
fluorophenylboronic acids, there are only two known ex-
amples. In one case 2,3,4,5-tetraflouroboronic acid is cou-
pled to 2-bromopyridine43 and in the other one the corre-
sponding neopentylester is coupled three times to 1,3,5-
triflouro-2,4,6-triiodobenzene.47 Pentafluoroboronic acid
is a very special case due to its inactivity under most Suzu-
ki-Miyaura coupling conditions. It can only be coupled in
the presence of CsF and Ag2O.48 The main problem of these
fluorinated phenylboronic acids is the rapid deboronation
under basic conditions which can be circumvented by
elaborate precatalysts such as second generation pal-
ladacycles developed by Buchwald and coworkers.49 As an
alternative to polyfluorophenylboronic acids, lithium
R
X
R
Fn
R'
Fm
+
B
R'
Fm
Fn
THF
n= 1-2
m= 1-2
Hird et al. 1999
Pd(PPh3)4
Na2CO3
HO
HO
X
+
B
Fn
Fn
EtOH, benzene, H2O
n= 3
Schlosser et al. 2003
Pd NH2
9
XPhos
Cl
10
11
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60
HO
HO
K3PO4
THF
X
+
B
R
R
Fm
Fm
m= 2-3
Buchwald et al. 2010
This Work
Pd2(dba)3
phosphine-ligand
K2CO3
HO
HO
X
+
B
Fn
Fn
Fm
Fm
m= 2-4
THF/toluene/H2O (3:3:1)
n= 3-5
To summarize the state of the art, to date no general meth-
od for the synthesis of highly fluorinated biaryls has been
published (Scheme 1). While former investigations have
found ways to introduce one fluorinated phenyl ring into a
biaryl or similar system, there has not been much progress
in the synthesis of fluorinated biaryls with fluorine atoms
on both phenyl rings. This is particularly true for biaryl
systems containing more than four fluorine atoms. In our
previous studies, it was already shown for these isolated
cases that it is possible to synthesize polyfluorinated ter-
phenyls14 and quaterphenyl13 with very high fluorine con-
tent and we were interested if these results can also be
applied to the synthesis of biphenyl systems. In that re-
spect, our motivation was not only to find a general way to
synthesize polyfluorinated biphenyls and making these
compounds better accessible - or, depending on the struc-
ture, accessible at all -, but also to find a methodology
which is reliable, reproducible, scalable, easy to handle and
needs no elaborate and expensive reagents or precatalysts.
Likewise, our emphasis was also to avoid any side prod-
ucts, which in general results in easy workups. Conse-
quently, the Suzuki-Miyaura coupling was selected for our
studies, because of the mild reaction conditions, the easy
preparation and general stability of the boronic acid deriv-
atives, and the low toxicity of the involved boron com-
pounds and their byproducts.65 In addition the Suzuki-
Miyaura coupling exhibits a wide functional group toler-
ance which is important for the transferability of the
method to different systems.
polyfluorophenyltrimethoxyborates50
and
potassium
polyfluorophenyltrifluoroborates51-53 were proven to be
effective coupling partners in cross coupling reactions and
therefore were also able to introduce C6F5-groups into
polyaryl compounds. Since highly fluorinated compounds
are easier targets for hydrodefluorination compared to
less fluorinated compounds, this has been exploited in C-F
activation54-55. The high acidity of the corresponding hy-
drogens in these compounds can be used for C-H activa-
tion56-59 and in combination with arenediazonium salts this
was used for copper-catalyzed cross-coupling.60 During the
preparation of this manuscript Carrow and coworkers
published a study that used arenediazonium salts and
fluorinated boronic acids via a cationic transmetalation
pathway in a Suzuki-Miyaura coupling.61 Very recently Pd-
nanoparticals62 and photocatalysis63-64 have been applied
to the synthesis of polyfluorinated biphenyls. Especially
the latter was shown to be very useful for the introduction
of perfluoro phenyl moieties. However, these methods
seem to be restricted to electron-rich counterparts or in
the case of the Pd-nanoparticles to only a low degree of
fluorination.
In this paper the synthesis of various polyfluorinated bi-
phenyls is presented which are in most cases unknown in
literature. Reaction conditions were optimized and a set of
catalyst-ligand systems was developed which performed
the desired cross coupling reactions and avoided side reac-
tions. Our goal was to introduce a synthetic toolkit to vari-
ous electron poor bi- and polyphenyl compounds which
has applicability beyond the presented results.
Results and Discussion
In the first part of this paper we will have a closer look on
the palladium catalyzed reaction between iodinated com-
pound 1 and boronic acid 2 (Scheme 2) and explain how
Scheme 1. Synthesis of polyfluorinated Biphenyls via
the Suzuki-Miyaura cross coupling.
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different reaction parameters influence this reaction. In
the second part these results are extended towards the
1
2
3
4
5
6
7
8
Table 1. Initial Screening of the reaction conditions for the
Benchmark Reaction.
coupling of various polyfluorinated iodine and boronic
acid compounds. Further we investigate the application of
different classes of organoboron compounds to circumvent
different side reaction and improve the methodology fur-
ther. Finally, we have a look at the electrophile and discuss
the boundaries of the presented methodology.
entrya
ligand
base
time
Pd/ligand
ratiob
homo-
couplingd
yield
1
SPhos
SPhos
SPhos
XPhos
XPhos
XPhos
XPhos
SPhos
XPhos
SPhos
Na2CO3
K2CO3
Cs2CO3
Na2CO3
K2CO3
Cs2CO3
K2CO3
K2CO3
K2CO3
K2CO3
14h
14h
14h
14h
14h
14h
60h
60h
60h
60h
1:2.5
1:2.5
1:2.5
1:2.5
1:2.5
1:2.5
1:2.5
1:2.5
1:1.5
1:1.5
5%
2%
3%
2%
-
36%
60%
39%
44%
35%
44%
85%
90%
99%
89%
2
3
4
Benchmark Reaction: Reaction between 2,3,4,5-
tetrafluoro-1-iodobenzene and 3,4,5-trifluorophenyl-
boronic acid. Since the aim was to find a general way to
synthesize polyfluorinated aromatic polyphenyls, we were
interested in the single coupling between two reaction
partners to build up a biaryl system. Compared to previous
research in which polyfluorinated ter- and quaterphenyl
compounds were synthesized, we encountered the prob-
lem that the formed side products were not separable from
the product by using standard purification methods. Even
more elaborate techniques, such as HPLC, did not give
satisfying results and are far from practicable on a larger
scale. Therefore, conditions had to be found in which all
side reactions can be avoided and both coupling partners
can be used in a 1:1 ratio. This should make this methodol-
ogy more appealing for more complex structures, since the
synthesis of the coupling partners can be a multi-step syn-
thesis, too. Also, using one coupling partner in excess has
the potential of promoting the formation of side products.
5
9
6
1%
-
10
11
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13
14
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22
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52
53
54
55
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58
59
60
7c
8c
9
2%
-
10
-
aReactions (except entry 10 and 11) were performed on a 0.18
mmol scale with 1 equiv. of 1 and 2 and 2.2 equiv. of the Base at
95°C. bAs Pd source 5% Pd2(dba)3 was used resulting in 10%
catalyst load. cThese reactions were performed on a 1.8 mmol
scale with 1 equiv. of 1 and 2 and 2.2 equiv. of the Base and 3%
Pd2(dba)3. dHomocoupling was determined by GC or 19F-NMR.
In a first step towards the optimization, the influence of
the base with three different phosphine ligands e.g. XPhos,
SPhos and XantPhos (Figure 1) were investigated. As bases
Na2CO3, K2CO3 and Cs2CO3 were chosen. While the use of
SPhos (up to 60%) and XPhos (up to 44%) resulted in
product formation (Table 1), with XantPhos no conversion
occurred.
Scheme 2. Initial Benchmark Reaction.
Although only different carbonate bases were tested (Ta-
ble 1), the impact of the cation was meaningful. In the
cases of XPhos, as well as SPhos, the lowest amount of the
homocoupling side product 4 was found with K2CO3 as
base (entries 2 and 5). And even if the differences are
small, they still are significant and important to obtain
pure product. In the case of XPhos with K2CO3 no side
products were found. In contrast to K2CO3, the reaction
with Na2CO3 exhibited the highest side product formation,
although still very low with only 2%. Cs2CO3 was found to
be in between Na2CO3 and K2CO3. Concerning product for-
mation, K2CO3 was better in the case of SPhos (60%) com-
pared to XPhos (35%). Na2CO3 and Cs2CO3 were in terms of
yield very similar in both the XPhos (44% vs 44%) and the
SPhos (36% vs. 39%) case. Therefore K2CO3 was identified
as the best in our selection, because it had a positive influ-
ence on reducing the homocoupling. This is in accordance
with Amatore and Jutand who have shown that the palla-
dium-catalyzed Suzuki–Miyaura reaction can be modulat-
ed by the countercation and that K+ as countercation has
the least rate decelerating effect in the transmetalation
reaction for carbonate bases.67 Stronger bases were not
investigated, since fluorinated phenylboronic acids are
more likely to undergo hydrodeboronation under more
basic conditions even at room temperature.68 As alterna-
tives fluoride ions could be of interest, which was shown
by Amatore and Jutand, but were not tested.69 Buchwald
and coworkers have shown that different 3-fold fluorinat-
ed boronic acids deboronate in THF with K3PO4 as base
within 10 minutes, stressing the point of an efficient cata-
lytic system for these kind of reactions.
Our initial experiment was to couple tetrafluoroiodoben-
zene 1 with trifluoroboronic acid 2 which should result in
the biphenyl 3. This reaction was chosen since the product
3 was easily distinguishable from other side products,
foremost homocoupling, by GC/MS due to their mass dif-
ference and by 19F-NMR because of the symmetry in the
side products. As palladium precatalyst Pd2(dba)3 with
XPhos (Figure 1) as ligand and Na2CO3 as base was select-
ed (Scheme 2). This was done in a THF/toluene/H2O mix-
ture (3:3:1) at 95°C for 16h. 66 These conditions were anal-
ogous to the conditions for the synthesis of our previously
published terphenyls. However, the yields were much
lower (36% for 3 compared to 90% for the terphenyl),
although only a single coupling had to be performed com-
pared to two couplings in the terphenyl case. The bigger
issue, however, was the occurring homocoupling of the
boronic acid to biphenyl 4. This compound was not sepa-
rable from the product by any common purification tech-
nique, due to its similar physical properties and primarily
polarity. Especially the apolar character makes normal
phase column chromatography impossible.
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2
XPhos
Cy
0.18
0.18
0.18
0.18
0.18
0.18
0.18
0.18
0.18
0.18
0.18
0.18
0.18
0.18
0.18
0.18
0.18
0.18
32
-
-
-
99%
What also should be taken into consideration is the influ-
ence of the solvent system, which also plays a significant
role, especially since a biphasic system was chosen. Tolu-
ene for example might lower the solubility of iodine salts in
the organic phase which could be important for the accel-
eration of the reaction. The role of THF potentially could
be that it stabilizes the electron-poor boronic acid and
therefore slows down the deboronation. Also important
for reducing the homocoupling was a long prestirring of
the Pd-precatalyst with the ligand before adding the reac-
tants and the exclusion of air to avoid oxidative homocou-
pling.70-72
3
DavePhos
MePhos
Cy
-
70%
82%
80%
98%
38%
87%
31%
14%
39%
88%
48%
51%
95%
29%
74%
83%
78%
95%
99%
1
2
3
4
5
6
7
8
4
Cy
-
-
5
RuPhos
Cy
-
-
6
CyJohnPhos
JohnPhos
PhDavePhos
tBuDavePhos
Me4tBuXphos
tBuXPhos
sSPhos
Cy
-
-
7
t-Bu
Ph
5%
8%
3%
23%
11%
24%
6%
17%
6%
3%
33%
11%
-
8
-
9
t-Bu
t-Bu
t-Bu
Cy
3%
10
11
12
13
14
15
16
17
18
19
20
21
20%
-
9
-
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
tBuMePhos
rac-BINAP
P(pCF3Ph)3
dppbz
t-Bu
Ph
4%
-
In further experiments the catalyst load was reduced to 3
mol% Pd2(dba)3 instead of 5% (Table 1, entries 4 and 5). In
the case of SPhos 1 was completely converted after 14h,
while with XPhos 1 was still present (determined by
GC/MS). This suggest that the reaction with XPhos is slow-
er and therefore the reaction time was extended to 60 h.
This led to improved yields with both SPhos (90%) and
XPhos (85%). The longer reaction time is not too surpris-
ing since XPhos is much more sterically hindered73. Based
on these results the mol fraction of Pd2(dba)3 was in-
creased to 5 mol% which equals 10 mol% catalyst load.
This high catalyst load is justified by the mentioned insta-
bility of the fluorinated phenylboronic acids under basic
conditions. Another improvement was made by shifting
the ligand/precatalyst ratio. In the first experiments a
1:2.5 ratio was used as suggested by standard Suzuki-
Miyaura procedures.74 However, a 1:1.5 metal to ligand
ratio resulted in higher yields and less formation of the
homocoupling product (Table 11, entries 5 and 6). This has
already been reported for various palladium catalyzed
cross-coupling reactions75-76 and has led to the develop-
ment of different generations of palladacyclic
pCF3Ph
Ph
1%
-
-
-
-
-
-
dppe
Ph
PCy2Ph
Cy
PCy3
Cy
11%
-
CyJohnPhos
CyJohnPhos
Cy
Cy
32
-
aReactions were performed with 1 equiv. 1 and 2 and 2.2 equiv. of
Na2CO3 with 5 mol% Pd2(dba)3 and a 15 mol% of the correspond-
ing ligand at 95°C for 60h on a 0.18 mmol scale. bHomocoupling
was determined by GC or 19F-NMR (given as percent of product
mixture).
As a general trend, it was found that ligands containing
PCy2 are less likely to form side products. Six different
Buchwald-ligands, containing this motif, formed no or only
traces of side products (Table 2, entry 1-6). The only ex-
ception was sSPhos which is difficult to compare to the
other ligands due to the sulfonic acid group resulting in a
better water solubility. In the biphasic solvent system, this
effectively reduces the catalyst concentration in the organ-
ic phase, which could favor side product formation. How-
ever, the yield of product (88%) is still comparable to the
original SPhos (89%). The tested ligands which contained
either PPh2 or P(t-Bu)2 groups generally showed side
product formation, though varying over a large range from
3% in the case of PhDavePhos to 33% in the case of dppbz.
To some extent the yield correlates negatively to the side
product formation. Minor exceptions are rac-BINAP and
JohnPhos which exhibit very low yields (51% and 38%)
although comparably little side product formation (6% and
13%) was observed. This also applies to DavePhos which
exhibits a yield of 70% even though no side product is
formed with that ligand. The low conversion is probably
due to a low turnover of the catalyst. Hence, deboronation
of the boronic acid can take place and reduce the yield.
This could of course be solved by adding more boronic acid
or adding it slowly over time. However, this would be less
practicable and can potentially even enable side product
formation. Still DavePhos is a valuable ligand for the cou-
pling of this type of compounds since the avoidance of side
product formation is of utter importance due to the sepa-
ration issue mentioned before. On the other hand, there
are also ligands which perform very well in terms of yield -
e.g. P(pCF3Ph)3, PhDavePhos and sSPhos (95%, 87% and
88%) - but are still less suitable because of side product
formation (4%, 3% and 6%). Looking at the formed side
products, predominantly the boronic acid is homocoupled.
In only few instances homocoupling of the iodine com-
precatalysts77-79
.
Benchmark Reaction: Ligand Screening. In the begin-
ning, the ligand screening focused on different Buchwald
ligands (Figure 1) since XPhos and SPhos showed promis-
ing results and because Buchwald ligands, with their bulky
groups and therefore large cone angles80-82, are beneficial
for the reductive elimination step.83-85 However, the
screening was also extended to other monodentate and
bidentate ligands. Every tested ligand induced product
formation, even though very different types of phosphines
(Figure 1) were used (Table 2, entry 1-17). The yield how-
ever varied widely from very low (14%) to 99%. This
clearly demonstrates the key role of the respective ligand.
More importantly, the choice of ligand is also crucial for
the prevention of side product formation.
Table 2 Ligand Screening for Benchmark Reaction.
K2CO3
Ligand
F
F
F
F
F
F
F
HO
HO
Pd2(dba)3
+
I
B
F
F
THF, Toluene, H2O (3:3:1)
60h, 95°C
F
F
F
F
F
3
1
2
2
entrya
1
ligand
-PR2
Scale
homocoup-
lingb
yield
(mmol)
1 (I)
2 (B)
SPhos
Cy
0.18
-
-
89%
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The Journal of Organic Chemistry
pound occurred and only with Me4tBuXphos it surpassed two to five fluorine atoms with different substitution pat-
1
2
3
4
5
6
7
8
the homocoupling of the boronic acid.
terns. As electrophile 1 was used for all experiments to get
a better understanding on the influence of the boronic acid,
while still obtaining very electron poor biphenyls.
An important question which should be answered is
whether the side product formation originates from the
steric or electronic properties of the ligands used. In two
comparison experiments PCy2Ph or PCy3 were used as
ligands (Table 2, entries 18 and 19). Both ligands gave
good yields (83% and 78%), but only with PCy2Ph no side
products were formed. This indicates that the steric influ-
ence of the biphenyl residue in the Buchwald-ligands is not
the decisive part in terms of side product formation. How-
ever, it still could be an important factor in the acceleration
of the reaction, since some of the Buchwald-ligands gener-
ated higher yields. Since PCy3 also created side products, it
can be concluded that the combination of two cyclohex-
anes and one phenyl ring is very favorable for the selective
product formation. Whether this originates from the steric
influence of the cyclohexene rings or their electronic prop-
erties cannot be answered. Considering that the very steri-
cally demanding XPhos and the simpler CyJohnPhos result
in a very similar outcome of nearly quantitative yield, it
seems that the electronic properties play a more substan-
tial role. In our final experiments, we were interested in
the scalability and reproducibility of our benchmark reac-
tion under optimized conditions. Therefore, CyJohnPhos
was tested on a 32 mmol scale, which is roughly a scale up
of 18000%. Although XPhos performs slightly better dur-
ing the screening, CyJohnPhos was chosen for the scale up
simply out of economic reasons, since CyJohnPhos is
cheaper per mol compared to XPhos. In two identical ex-
periments 95 and 99% yield were obtained, respectively.
This shows that this reaction is scalable and reproducible
with high yields, and still no side products were formed.
At first, only CyJohnPhos was tested for the coupling of
different boronic acids as it was found to be a very efficient
ligand in the benchmark reaction (Table 3). However, alt-
hough CyJohnPhos lead to virtually quantitative product
formation with boron acid 2 (98%), it did not perform well
in all reactions. While the coupling of 1 and 5 still yielded
88% of the corresponding biphenyl, the coupling with
boronic acids 6-8 only yielded 31 to 40% (Table 3). The
coupling with 9 did not even from any product at all. Espe-
cially interesting was the coupling with the boronic acid 6
and 7, because the formation of the corresponding homo-
coupling compounds was observed.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
For the explanation of these results two considerations
must be taken into account: On the one hand, the hydrode-
boronation rate and on the other hand, the transmetalation
rate of the boronic acids. Both are influenced by the elec-
tron withdrawing fluorine atoms, which means higher
hydrodeboronation and higher transmetalation rate with
increasing fluorine substitution. This is even more chal-
lenging if the fluorine atoms are present in ortho position
to the boronic acid. The latter results in a faster transmeta-
lation reaction, which was investigated by Buchwald and
coworkers.49 They found that compared to phenylboronic
acid, even one fluorine atom in ortho position can poten-
tially increase the relative transmetalation rate 42-fold.
This effect is less distinct in the meta (2-fold) and para (5-
fold) position, but this can add. Opposing to that the com-
peting hydrodeboronation is also accelerated by electron
withdrawing fluorine atoms. Frohn and coworkers report-
ed for 2 that it does not hydrodeboronate in the presence
of 9% pyridine in water, even at 100 °C.68 Yet, if a fluorine
atom in the ortho position is added (2,3,4,5-
tetrafluorophenylboronic acid), this results in a deborona-
tion within 50 min and in the case of 8 it only takes 60 min
at 32 °C. Even very low fluorinated derivatives such as 2,4-
difluorophenylboronic acid decompose over time (53% in
19 hours). This is of course most be predominant in the
case of 9, which decomposes within 2-5 minutes at 25 °C.
This explains why it was not possible to couple 9.
Buchwald-Ligands
PR2
PR2
PR2
PCy2
O
N
O
iPr
iPr
R = tBu = JohnPhos
R = tBu = tBuMePhos R = tBu = tBuDavePhos
RuPhos
R = Cy = CyJohnPhos R = Cy = MePhos
R = Cy = DavePhos
R = Ph = PhDavePhos
Monodentate
Ligands
P(tBu)2
iPr
PR2
iPr
PCy2
iPr
iPr
MeO
OMe
P
CF3
3
Table 3. Coupling of different fluorinated boronic acids to
iPr
Me4tBuXPhos
R
iPr
P(pCF3Ph)3
2,3,5,6-tetrafluoroiodo-benzene.
R = tBu = tBuXPhos
R = Cy = XPhos
R = H = SPhos
R= SO3Na = sSPhos
P
Bidentante Ligands
3
PPh2
PCy3
PPh2
PPh2
PPh2
dppbz
P
entrya
1
boronic acid
product
CyJohnPhos
yield
optimized
yield (Lig-
and)
O
2
PPh2
PPh2
Ph2P
PPh2
PCy2Ph
XantPhos
rac-BINAP
dppe
98%
98%
Figure 1. Ligands used in the screening of the benchmark reac-
tion.
(CyJohnPhos
2
88%
99%
Screening of boronic acid derivatives as nucleophiles.
In the next step, the investigation was extended towards
other boronic acid derivatives. To this end, different fluor-
inated boronic acids were chosen which comprise from
(XPhos)
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The Journal of Organic Chemistry
Page 6 of 17
3
4
5
6
35%b
40%b
31%
-
47%
phile. In this control experiment only 19% of the homo-
coupled product was obtained which suggests that mainly
(RuPhos)
1
2
3
4
5
6
7
8
cross coupling was responsible for the product formation.
Interestingly, MePhos did not provide any product even
though with CyJohnPhos 31% was obtained, which is
noteworthy considering the structural resemblance of both
ligands. However, these results were reproducible. In the
case of boronic acid 9 the ligand screening did not lead to
product 14.
28%
(XPhos)
58%
(DavePhos)
Influence of Boronic Acid Protecting Groups on the
Coupling of Electron Poor Biphenyls. Since it can be
assumed that one main issue is the already discussed in-
stability of the boronic acid derivatives, the screening was
exteded towards different organoboron electrophiles,
namely neopentyl glycol boronic esters86 and MIDA(N-
methyliminodiacetic acid)-boronates87. Alternative boron
nucleophiles are known to be more stable under most
Suzuki-Miyaura conditions than the corresponding boronic
acids. However, it is not known how the actual reaction
mechanism proceeds and whether they react either direct-
ly as nucleophile or via the boronate pathway.88 Since our
solvent system contains large quantities of water, our
working hypothesis was that the protected boronic acid is
hydrolyzed over time, generating the free boronic acid
which afterwards reacts as commonly known.89
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
-
aReactions were performed with 1 equiv. 1 and the corresponding
boronic acid and 2.2 equiv. of Na2CO3 with 5 mol% Pd2(dba)3 and
a 15 mol% of the corresponding ligand at 95°C for 60h on a 0.18
mmol scale. bContains significant amounts of a homocoupling side
product (>2%).
Since CyJohnPhos did not perform well in all reactions, the
screening was extended towards other Buchwald ligands
which contain the PCy2 group due to their low side product
formation in the benchmark reaction. The chosen ligands
were MePhos, RuPhos, XPhos, SPhos and DavePhos. In
most cases the screening improved the yields significantly
and more important, ligands were found which exhibit no
side product formation (Table 3). All obtained screening
data can be found in the Supporting Information (Table
S1).
Table 4. Optimized results after ligand screening for the
coupling of different fluorinated protected boronic acids to
2,3,5,6-tetrafluoroiodo-benzene.
With 6 the coupling exhibited much lower yields, but still,
the screening of the ligands improved the yield significant-
ly from 35% with CyJohnPhos to 48% with SPhos. More
importantly, the screening of the ligands solved the homo-
coupling issues. In the case of RuPhos (Table 3, entry 3)
and XPhos no homocoupling was found and similar yields
were obtained with 47% and 45%. The homocoupling
products which were found in the other cases were due to
the homocoupling of compound 1 resulting in product 13.
This suggests that the hydrodeboronation is very fast re-
sulting in the homocoupling of the electrophile instead of
the nucleophile.
entrya
1
protected boronic
acid
ligand
product
yield
DavePhos
84%
2
CyJohnPhos
80%
The importance of the ligand choice can also be seen in the
reaction of 7 and 8 with 1. With 7 as electrophile the yield
could be increased from 40 to 86%. However, the obtained
product 12 was not pure and 8% of the homocoupled bi-
phenyl (electrophile) was found. This still could be viable,
if the yield of the product is more important than the puri-
ty, but if purer product is needed, CyJohnPhos can be used
to obtain 40% product without any side product for-
mation. For the synthesis of 13 with boronic acid 8 the
yields varied from no yield at all with MePhos to 58% with
DavePhos (Table 3, entry 5). In the case of SPhos and
RuPhos unknown side product were formed which could
not be identified. In the case of DavePhos pure product
was obtained and the yield with 58% was still very good
considering the coupling of a boronic acid with two fluo-
rine atoms in ortho position. Since it is not possible to
differentiate between homocoupling and cross coupling, a
comparison experiment was done without 1 as electro-
3
4
RuPhos
MePhos
63%
82%
5
DavePhos
62%
aReactions were performed with 1 equiv. 1 and the corresponding
boronic acid and 2.2 equiv. of Na2CO3 with 5 mol% Pd2(dba)3 and
a 15 mol% of the corresponding ligand at 95°C for 60h on a 0.18
mmol scale.
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The Journal of Organic Chemistry
Initially both the neopentyl glycol boronic ester 15 and the chosen. From previous experiments in our studies with
1
2
3
4
5
6
7
8
MIDA-boronate 16 of boronic acid 7 were tested since this
boronic acid was especially susceptible towards homocou-
pling.90 (Table 4, entries 1 and 2) In all cases tested with
both protecting groups, no homocoupling was found and
the yields were significantly better compared to the cou-
pling of the free boronic acid. The best yields were ob-
tained with 15 as nucleophile and DavePhos as ligand
(84%). Although even more stable, the corresponding
MIDA-derivative did not improve the reaction further
(80% yield with RuPhos or CyJohnPhos). Complete screen-
ing data can be found in the Supporting Information (Table
S2).
ter- and quaterphenyl compounds we already knew that
the corresponding boronic acid is too instable for the cou-
pling and even the ester had to be used in large excess for
reasonable yields.13 However, DavePhos produced good
yields (62%) even in a 1:1 stoichiometry. All other ligands
performed much weaker with only 10-24%, again empha-
sizing how important the ligand screening is.
Extending the Screening towards Different Electro-
philes. In our last experiments, we wanted to have a look
how our obtained results can be applied to other electro-
philes. Since our method failed to couple boronic acid 9, it
was examined if pentafluoroiodobenzene can be used as
electrophile to introduce a C6F5 group and whether there is
an upper limit in terms of the fluorination grade. The lig-
ands were chosen according to our previous experiments
based on the boronic acid or ester that was used, with the
hypothesis that the interplay between the boronic acid and
the ligand is the decisive factor. This approach should be a
viable starting point for all future couplings. (Table 5, en-
tries 1-10). Additionally, it was of interest to find out if it is
possible to substitute the iodine in the electrophiles with
bromine (Table 5, entries 11-18) or chlorine (Table 5,
entry 3), since the bromine compound is often the precur-
sor for the iodine compound and brominated compounds
are more often commercially available. In the end we also
extended our scope to different highly fluorinated pyridine
compounds to include heterocycles.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
These results encouraged us to extend this strategy to
other boronic acids (Table 4). Since the neopentyl glycol
boronic esters and the MIDA-boronate were very similar in
their outcome, but the neopentyl glycol boronic esters are
easier to prepare, we chose them for our further investiga-
tions. However, the MIDA-boronates could still be valuable
for similar couplings. In the case of boronic acid 6, prob-
lems occurred with the homocoupling of 1 with four out of
the six ligands. The use of the boronic acid ester did not
solve this problems for these ligands, but still, the actual
amount of the homocoupling decreased significantly. For
example, in the case of CyJohnPhos the homocoupling was
reduced from 30% to 7% while the yield increased from
35% to 78%. The yield also increased for MePhos,
DavePhos and RuPhos, while with XPhos and SPhos
around 20% lower yields were observed. A similar obser-
vation was already made in the case of product 12, where
the performances of XPhos and SPhos (51-61%) were
weaker compared to the other ligands (68-84%) (see Sup-
porting Information, Table S2, entries 1-12). For the Syn-
thesis of 11 with RuPhos no side product formation and
the yield went up from 27% to 63%. This advocates that
increasing the stability of the boronic acid is a useful strat-
egy.
Table 5. Influence of the electrophile in different Suzuki-
Miyaura couplings for the synthesis of highly fluorinated
biphenyls.
Pd2(dba)3
phosphine-ligand
R
R
K2CO3
X
+
B
Fn
Fn
Fm
Fm
THF/toluene/H2O (3:3:1)
n= 3-5
m= 2-4
The synthesis of biaryl 13 was also improved significantly
by the use of the neopentyl glycol boronic ester (Table 4,
entry 4). While the best yield with boronic acid 8 was 58%
with DavePhos, the yield was increased to 82% with 18 as
nucleophile and MePhos as Ligand. CyJohnPhos, DavePhos
and RuPhos showed much lower Yields with 10-39%. In
the cases of XPhos and SPhos in the presence of the ester
no yield was observed. In general, it was observed that
XPhos and SPhos, if used in combination with a boronic
ester, are the worst performing ligands within our selec-
tion. In most cases they perform significantly worse with
the esters as with the free boronic acids. This result is very
interesting since it means that the protected boronic acid
could also be directly involved in the transmetalation and
not necessarily only the boronic acid. Therefore, very
bulky ligands like XPhos and SPhos could slow down the
transmetalation in combination with more sterically de-
manding protecting groups. All screening results can be
found in the Supporting Information (Table S2 and S3).
en-
electrophile
nucleophile
product
(ligand)
yield
trya
1
(homocou-
plingb)
21
83%
(1%)
(XPhos)
2
3
4
22
43%
74%
37%
(5%)
(3%)
(CyJohn-
Phos)
22
(CyJohn-
Phos)
23
(29%)
(Ru-
Phos)
5
6
24
18%
99%
(33%)
(Dave-
Phos)
Since the use of the neopentyl boronic ester has been
proven to be a valuable strategy for the cross coupling of
electron-poor biphenyls, it was interesting to see if this
strategy can be applied to synthesize an even more chal-
lenging biphenyl. As coupling partners, 19 and 1 were
25
-
(CyJohn-
Phos)
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Page 8 of 17
7
8
26
51%
-
23
38
81%
98%
(12%)
(1%)
(Ru-
Phos)
(XPhos)
1
2
3
4
26
81%
-
24
39
(Ru-
Phos)
(CyJohn-
Phos)
5
aReactions were performed with 1 equiv. of the electrophile and
the nucleophile and 2.2 equiv. of Na2CO3 with 5 mol% Pd2(dba)3
and a 15 mol% of the corresponding ligand at 95°C for 60h. Ho-
mocoupling determined by GC and 19F-NMR (percentage in the
product mixture).
6
7
8
9
9
27
67%
-
b
(Dave-
Phos)
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
10
11
12
13
28
77%
83%
72%
73%
(2%)
In most experiments moderate to excellent yields were
obtained with only minor side product formation (<5%). In
general, the method performs well in the synthesis of bi-
phenyls with six or seven fluorine atoms, the side product
formation is very minor (<2%) and the yields are very
good (>51%). In these cases, it also seems that bromine
derivatives can be used without major disadvantages in
terms of yield and side product formation (Table 5 entries
11-18). However, iodine derivatives are still viable as can
be seen in entry 16 of Table 5 where the coupling with the
corresponding bromine compound is not nearly as good as
the corresponding iodine derivative (62% vs. 13%) which
corresponds with the instability of the used boronic acid. It
was also possible to introduce the C6F5 moiety into the
biphenyl compounds (Table 5, entry 1, 5 and 6), but the
yields decrease with the instability of the boronic acid
derivative and the amount of homocoupling increases.
With more stable boronic acids (2) even chlorinated sub-
strates can be used for the coupling. With nine fluorine
atoms in total (Table 5, entry 6) the obtained yield was
only 18% with 33% of the mixture being the homocou-
pling product. Still, this is the first time a coupling of a
biphenyl with nine fluorine atoms is reported under Suzu-
ki-Miyaura conditions. In addition we extended our scope
towards polyfluorinated pyridines and obtained between
36% and 98% yield, depending on the substitution pattern
(Table 5, entries 19-24). Only in one case homocoupling
was observed (12%).
(CyJohn-
Phos)
4
-
-
-
(CyJohn-
Phos)
29
(CyJohn-
Phos)
30
(Ru-
Phos)
14
15
31
95%
77%
(2%)
-
(CyJohn-
Phos)
32
(Ru-
Phos)
16
20
13%
-
(Dave-
Phos)
17
18
3
81%
83%
(<1%)
-
(CyJohn-
Phos)
33
(CyJohn-
Phos)
Conclusion
The main goal of this research was to find a general and
reliable way to synthesize various polyfluorinated biphen-
yls. By vigorous testing of different phosphines and reac-
tion conditions we found a set of different ligands which
were not only capable of synthesizing our target mole-
cules, but also of producing them without any major side
products, resulting in pure product after a simple work up.
For every fluorinated boronic acid or ester a ligand was
found which can couple it to various electrophiles. Espe-
cially the ligands containing an Aryl-PCy2 group were very
suitable for these couplings and we showed how different
boronic acid protecting groups can improve yields and
reduce side product formation. We also found that a viable
starting point for every coupling is to choose the ligand
that is best for the respective boronic acid or ester. This
should facilitate the synthesis of various unknown and
more functionalized polyfluorinated biphenyls.
19
20
21
34
65%
84%
72%
(2%)
-
(XPhos)
35
(CyJohn-
Phos)
36
(2%)
(CyJohn-
Phos)
22
37
36%
(<1%)
(Dave-
Phos)
In summary, a wide range of different polyfluorinated
biphenyls, many of them unknown in literature, have been
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The Journal of Organic Chemistry
synthesized by using Suzuki-Miyaura cross-coupling. By per and heated to 95°C for 60h. After cooling to room tem-
1
2
3
4
5
6
7
8
extending the accessibility of various polyfluorinated bi-
phenyls they can now be used as building blocks for vari-
ous applications in material science and supramolecular
chemistry.
perature, the aqueous phase was removed with a Pasteur
pipette and the organic solvents were removed in vacuo.
The residue is resuspended with 5ml pentane and silica is
added to the mixture. Afterwards the solvents are again
removed in vacuo. This should be done with care due to the
volatile nature of the corresponding products. The residue
is filtered through a plug of silica with pentane as eluent.
Pentane was removed in vacuo and the corresponding
polyfluorinated biphenyl was obtained as white solid. For
all tested ligands please refer to the Supporting Infor-
mation . In the following only the best ligands in each case
are listed.
Experimental Section
General Methods. All reactions except the boresterfica-
tions were performed under an atmosphere of argon by
using standard Schlenk techniques. 1H, 11B, 19F and
C12H3F7-NMR spectra were recorded on either Bruker
Avance III 300, Avance III 400 DPX 250 or DRX 400 spec-
trometers at 22 °C. All shift values are in ppm and all cou-
pling constants (J) are printed in Hertz (Hz) with their
multiplicity: s (singlet), bs (broad singlet), d (doublet), t
(triplet), q (quartet), m (multiplet), dd (doublet of dou-
blet). GC/MS spectra were measured on a Hewlett Packard
5972 GC/MS System equipped with a Phenomenex Zebron
ZB-5HT Inferno (25 m) column. Mass spectra of GC/MS
unsuitable molecules were measured on a Jeol AccuTOF
GCv with electron ionization (EI) as ionization technique.
Infrared spectra were obtained on a Shimadzu FTIR-8400s
spectrometer equipped with a Specac Quest ATR through
attenuated total reflection (ATR). Elemental analysis were
performed on a vario MICRO cube from Elementar Analy-
sensysteme GmbH.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
2,3,3',4',5,5',6-Heptafluoro-1,1'-biphenyl (3): Following
the general procedure with 1,2,4,5-tetrafluoro-3-
iodobenzene (1), (3,4,5-trifluorophenyl)boronic acid (2)
and XPhos as phosphine ligand. The desired product was
obtained as white solid (50,2 mg, 99%). Alternative Pro-
cedure: Following the general procedure with 3-Bromo-
1,2,4,5-tetrafluorobenzene and CyJohnPhos as phosphine
ligand. The reaction was done on a 0.44 mmol scale. The
desired product was obtained as white solid (99 mg, 81%).
1H-NMR: (250 MHz, Chloroform-d) δ 7.15 – 6.93 (m).
13C{1H}NMR: (101 MHz, Chloroform-d) δ 151.4 (ddd, J =
251.0, 10.1, 4.2 Hz), 146.4 (dddd, J = 249.2, 14.7, 10.3, 4.1
Hz), 143.7 (ddt, J = 248.7, 14.3, 4.0 Hz), 140.4 (dt, J = 255.5,
15.1 Hz), 123.8 – 122.7 (m), 118.6 (t, J = 15.8 Hz), 115.4 –
114.3 (m), 106.2 (t, J = 22.6 Hz). 19F{1H}NMR: (235 MHz,
Chloroform-d) δ -133.34 (d, J = 20.5 Hz), -137.41 – -138.40
(m), -142.83 – -144.21 (m), -158.26 (t, J = 20.5 Hz). FTIR
(ATR): see Supporting Information. MS (EI+): calc´d for
C12H3F7 [M]+: 280.0; found 279.9. EA: calc´d C, 51.45; H,
1.08; N, 0.00 found C, 51.51; H; 0.998; N, 0.00. Rf: 0.9 (pen-
tane).
Materials. For all cross-coupling reactions solvents were
deoxygenated with the freeze-pump-thaw technique. An-
hydrous tetrahydrofuran (THF) and diethyl ether (DEE)
were obtained as technical grade, distilled prior use, dried
and purified with an MBraun MB-SPS-800 solvent purifica-
tion system and stored over molecular sieves (3 Å). The
THF and toluene for the cross-coupling reactions were
purchased as p. a. grade from Fisher Chemical and used
without further purification. Double distilled H2O (ddH2O)
was used for all cross-coupling reactions. All other solvents
were obtained as technical grade and used after simple
distillation. Deuterated solvents for NMR were purchased
from Euriso-top or Deutero and used as received. Boronic
2,3,3',5,5',6-hexafluoro-1,1'-biphenyl (10): Following
the general procedure with 1,2,4,5-tetrafluoro-3-
iodobenzene (1), (3,5-difluorophenyl)boronic acid (5) and
XPhos as phosphine ligand. The desired product was ob-
tained as white solid (47 mg, 99%). 1H NMR: (250 MHz,
Chloroform-d) δ 7.13 (tt, J = 9.7, 7.4 Hz, 1H), 7.02 (ddd, J =
6.5, 2.3, 1.2 Hz, 2H), 6.93 (tt, J = 8.9, 2.3 Hz, 1H).
13C{1H}NMR: (101 MHz, Chloroform-d) δ 163.0 (dd, J =
249.4, 12.9 Hz), 146.4 (dddd, J = 248.9, 14.7, 10.3, 4.1 Hz),
143.8 (ddt, J = 248.8, 14.3, 4.1 Hz), 130.3 (tt, J = 10.4, 2.4
Hz), 119.4 (tt, J = 16.1, 2.4 Hz), 113.8 – 113.3 (m), 106.1 (t,
J = 22.6 Hz), 105.0 (t, J = 25.1 Hz).. 19F{1H}NMR: (235 MHz,
Chloroform-d) δ -108.98 (s, 2F), -138.28 (dd, J = 21.8, 12.8
Hz, 2F), -143.32 (dd, J = 21.9, 12.9 Hz, 2F). FTIR (ATR): see
Supporting Information. MS (EI+): calc´d for C12H4F6 [M]+:
262.0; found 262.0. EA: Anal. Calcd for C12H4F6: C, 54.98; H,
1.54; N, 0.00; found C, 55.29; H; 1.507; N, 0.00. Rf: 0.9 (pen-
tane).
acids
5
[(3,5-difluorophenyl)boronic acid]91 and
8
[(2,3,5,6-tetrafluorophenyl)boronic acid]92 were synthe-
sized according to literature procedures. The boronic acid
ester (20) was synthesized as previously described by our
group.13 All other chemicals were obtained from either
Sigma-Aldrich, Carbolution, Fluorochem, Alfa-Aeser,
ACROS, ABCR or TCI Europe and used without prior purifi-
cation.
General Procedure for Suzuki-Miyaura coupling. Into
an argon-purged 10 ml Schlenk-tube deoxygenated THF (1
ml) and toluene (1 ml) was filled and 9 µmol Pd2(dba)3 (8,3
mg, 5 mol%) and 30 µmol of the corresponding phosphine
ligand (15 mol%) were dissolved. The reaction mixture
was stirred at 50 °C for 2 h to prepare the active catalyst.
This is indicated through a color change from deep red to
yellow, orange or green depending on the used phosphine
ligand. Afterwards 0.33 ml deoxygenated ddH2O and 0.36
mmol K2CO3 (50.1 mg, 200 mol%) was added, resulting in
a biphasic reaction mixture. Then the corresponding
polyfluorinated phenylboronic acid or ester (0.18 mmol)
and the polyfluoro- iodobenzene or bromobenzene (0.18
mmol) were added. The flask was sealed with a glass stop-
2,2',3,4',5,5',6-heptafluoro-1,1'-biphenyl (11): Follow-
ing the general procedure with 1,2,4,5-tetrafluoro-3-
iodobenzene (1), (2,4,5-trifluorophenyl)boronic acid (6)
and RuPhos as phosphine ligand. The desired product was
obtained as white solid (22.3 mg, 47%). Alternative Pro-
cedure: Following the general procedure with 1,2,4,5-
tetrafluoro-3-iodobenzene (1), 5,5-Dimethyl-2-(2,4,5-
trifluorophenyl)-1,3,2-dioxaborinane (17) and RuPhos as
phosphine ligand. The desired product was obtained as
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The Journal of Organic Chemistry
Page 10 of 17
white solid (32.0 mg, 63%). 1H NMR: (250 MHz, Chloro-
297.9. EA: Anal. Calcd for C12H2F8: C, 48.34; H, 0.68; N, 0.00;
found C, 48.35; H; 0.67; N, 0.00. Rf: 0.9 (pentane).
form-d) δ 7.62 – 6.90 (m). 13C{1H}NMR: (101 MHz, Chloro-
form-d) δ 155.3 (ddd, J = 250.3, 9.6, 2.7 Hz), 151.1 (ddd, J =
255.0, 14.2, 12.0 Hz), 146.8 (ddd, J = 246.7, 12.8, 3.8 Hz),
146.0 (dddd, J = 249.0, 14.6, 10.4, 4.2 Hz), 143.8 (ddt, J =
249.7, 14.3, 4.1 Hz), 119.66 (ddd, J = 20.4, 3.9, 1.9 Hz),
113.9 (t, J = 17.7 Hz), 111.4 – 111.1 (m), 106.6 (t, J = 21.5
Hz), 106.2 (d, J = 21.2 Hz). 19F{1H}NMR: (235 MHz, Chloro-
form-d) δ -113.47 (dtd, J = 14.5, 11.0, 5.5 Hz), -130.09 (dd, J
= 21.5, 5.5 Hz), -137.77 – -138.54 (m), -140.60 – -140.98
(m), -141.61 (dd, J = 21.5, 14.5 Hz). FTIR (ATR): see Sup-
porting Information. MS (EI+): calc´d for C12H3F7 [M]+:
280.0; found 279.9. EA: Anal. Calcd for C12H3F7: C, 51.45; H,
1.08; N, 0.00; found C, 52.65; H; 0.96; N, 0.00. Rf: 0.9 (pen-
tane).
1
2
3
4
5
6
7
8
2,2',3,3',4,5,5',6'-octafluoro-1,1'-biphenyl (20): Follow-
ing the general procedure with 1,2,4,5-tetrafluoro-3-
iodobenzene
(1),
5,5-Dimethyl-2-(2,3,4,5-
tetrafluorophenyl)-1,3,2-dioxaborinane (19) and DavePh-
os as phosphine ligand. The desired product was obtained
as white solid (33.5 mg, 62%). Alternative Procedure:
Following the general procedure with 1,2,4,5-tetrafluoro-
3-bromobenzene,
5,5-Dimethyl-2-(2,3,4,5-
9
tetrafluorophenyl)-1,3,2-dioxborinane (19) and DavePhos
as phosphine ligand. The desired product was obtained as
white solid (7.0 mg, 13%). 1H NMR: (250 MHz, Acetone-d6)
δ 7.62 (tt, J = 10.3, 7.6 Hz, 1H), 7.44 (tdd, J = 10.6, 7.1, 2.5
Hz, 1H). 13C{1H}NMR: (63 MHz, Chloroform-d) δ 147.4
(dddd, J = 248.5, 10.4, 3.8, 2.5 Hz), 148.2 – 143.5 (m), 148.8
– 144.1 (m), 144.1 (ddt, J = 250.1, 14.5, 4.1 Hz), 144.2 –
139.2 (m), 113.3 (ddt, J = 20.5, 3.7, 2.0 Hz), 113.2 – 112.1
(m), 111.7 (dddd, J = 13.0, 7.2, 4.5, 2.4 Hz), 107.3 (t, J = 22.6
Hz). 19F{1H}NMR: (235 MHz, Chloroform-d) δ -137.25
(dddd, J = 20.1, 11.1, 5.4 Hz, 1F), -138.38 – -138.67 (m, 2F),
-139.01 (ddd, J = 20.7, 12.0, 3.1 Hz, 1F), -140.81 – -141.58
(m, 2F), -153.17 (ddd, J = 20.8, 19.4, 5.4 Hz, 1F), -154.73
(td, J = 19.7, 3.1 Hz, 1F). MS (EI+): calc´d for C12H2F8 [M]+:
298.1; found 298.1. EA: Anal. Calcd for C12H2F8: C, 48.34; H,
0.68; N, 0.00 found C, 48.36; H; 0.89; N, 0.00. Rf: 0.9 (pen-
tane).
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
2,2',3,3',4,5',6'-heptafluoro-1,1'-biphenyl (12): Follow-
ing the general procedure with 1,2,4,5-tetrafluoro-3-
iodobenzene (1), (2,3,4-trifluorophenyl)boronic acid (7)
and XPhos as phosphine ligand. The desired product was
obtained as white solid (14.2 mg, 28%). Alternative Pro-
cedure: Following the general procedure with 1,2,4,5-
tetrafluoro-3-iodobenzene (1), 5,5-Dimethyl-2-(2,3,4-
trifluorophenyl)-1,3,2-dioxaborinane (15) and DavePhos
as phosphine ligand. The desired product was obtained as
white solid (42.4 mg, 84%). Alternative Procedure: Fol-
lowing the general procedure with 1,2,4,5-tetrafluoro-3-
iodobenzene (1) and the MIDA-boronate of (2,3,4-
trifluorophenyl)boronic acid (16) and CyJohnPhos or
RuPhos as phosphine ligand. The desired product was
obtained as white solid (40.4 mg, 80%). 1H NMR: (250
MHz, Chloroform-d) δ 7.25 – 7.05 (m, 3H). 13C{1H}NMR:
(63 MHz, Chloroform-d) δ 152.3 (ddd, J = 252.6, 9.9, 2.3
Hz), 149.5 (ddd, J = 254.4, 10.9, 3.4 Hz), 148.6 – 143.9 (m),
144.0 (ddt, J = 249.2, 14.2, 4.1 Hz), 140.7 (dt, J = 253.0, 15.3
Hz), 125.9 – 125.5 (m), 114.6 – 113.6 (m), 113.1 (dt, J = 4.8,
2.5 Hz), 112.73 (dd, J = 17.9, 3.9 Hz), 107.25 – 106.27 (m).
19F{1H}NMR: (235 MHz, Chloroform-d) δ -131.43 (dd, J =
20.6, 9.2 Hz), -132.14 (ddd, J = 19.9, 10.4 Hz), -138.30 – -
138.52 (m), -140.81 – -141.09 (m), -158.90 (t, J = 20.4 Hz).
FTIR (ATR): see Supporting Information. MS (EI+): calc´d
for C12H3F7 [M]+: 278.0; found 279.9. EA: Anal. Calcd for
C12H3F7: C, 51.45; H, 1.08; N, 0.00; found C, 51.44; H; 1.08;
N, 0.00. Rf: 0.9 (pentane).
2,3,3',4,5,5',6-heptafluoro-1,1'-biphenyl (21): Following
the general procedure with pentafluoroiodobenzene, (3,5-
difluorophenyl)boronic acid (5) and XPhos as phosphine
ligand. The reaction was done on a 0.36 mmol scale. The
reaction was done on a 0.36 mmol scale. The desired
product was obtained as white solid (87.4 mg, 95%). The
product contained <1 % of the corresponding homocou-
pling product. 1H NMR: (400 MHz, Chloroform-d) δ 6.98
(ddt, J = 7.7, 2.4, 1.2 Hz, 2H), 6.93 (tt, J = 8.8, 2.3 Hz, 1H).
13C{1H}NMR: (101 MHz, Chloroform-d) δ 163.1 (dd, J =
249.8, 12.8 Hz), 145.7 – 142.8 (m), 141.2 (dtt, J = 255.7,
13.4, 5.1 Hz), 139.6 – 136.6 (m), 129.2 (tdd, J = 10.5, 3.9,
1.8 Hz), 114.2 – 113.9 (m), 113.8 – 113.4 (m), 105.2 (t, J =
25.1 Hz). 19F{1H}NMR: (235 MHz, Chloroform-d) δ -108.59
(s, 2F), -142.15 – -143.59 (m, 2F), -153.35 (t, J = 20.9 Hz,
1F), -160.30 – -162.60 (m, 2F). FTIR (ATR): see Supporting
Information. MS (EI+): calc´d for C12H3F7 [M]+: 280.0; found
279.9. EA: Anal. Calcd for C12H3F7: C, 51.45; H, 1.08; N, 0.00
found C, 51.54; H; 1.09; N, 0.00. Rf: 0.9 (pentane).
2,2',3,3',5,5',6,6'-octafluoro-1,1'-biphenyl (13): Follow-
ing the general procedure with 1,2,4,5-tetrafluoro-3-
iodobenzene (1), (2,3,5,6-tetrafluorophenyl)boronic acid
(8) and DavePhos as phosphine ligand. The desired prod-
uct was obtained as white solid (31.3 mg, 58%). Alterna-
tive Procedure: Following the general procedure with
1,2,4,5-tetrafluoro-3-iodobenzene (1), 5,5-Dimethyl-2-
(2,3,5,6-tetrafluorophenyl)-1,3,2-dioxaborinane (18) and
MePhos as phosphine ligand. The desired product was
obtained as white solid (44.4 mg, 82%). 1H NMR: (250
MHz, Chloroform-d) δ 7.36 – 7.15 (m, 2H). 13C{1H}NMR:
(63 MHz, Chloroform-d) δ 148.6 – 143.7 (m), 146.4 – 141.9
(m), 108.1 (t, J = 22.1 Hz), one C missing. 19F{1H}NMR:
NMR (377 MHz, Chloroform-d) δ -137.66 – -137.85 (m,4F),
-138.20 – -138.42 (m, 4F). FTIR (ATR): 3068 (w), 1603
(m), 1510 (m), 1479 (s), 1437 (m)0, 1437 (m), 1227 (m),
1179 (m), 962 (m), 910 (m), 853 (m), 704 (m), 685 (m),
665 (m). MS (EI+): calc´d for C12H2F8 [M]+: 298.0; found
2,3,3',4,4',5,5',6-octafluoro-1,1'-biphenyl (22): Follow-
ing the general procedure with pentafluoroiodobenzene,
(3,4,5-trifluorophenyl)boronic acid (2) and CyJohnPhos as
phosphine ligand. The reaction was done on a 0.36 mmol
scale. The desired product was obtained as white solid
(51.8 mg, 43%). The product also contained 5% of the
corresponding homocoupling product. Alternative Pro-
cedure: Following the general procedure with chloropen-
tafluorobenzene, (3,4,5-trifluorophenyl)boronic acid (2)
and CyJohnPhos as phosphine ligand. The reaction was
done on a 0.49 mmol scale. The product also contained 3%
of the corresponding homocoupling product. The desired
product was obtained as white solid (109 mg, 74%). 1H
NMR: (250 MHz, Chloroform-d) δ 7.14 – 7.05 (m, 2H).
19F{1H}NMR: (235 MHz, Chloroform-d) δ -132.95 (d, J =
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The Journal of Organic Chemistry
20.5 Hz, 2F), -142.54 – -142.85 (m, 2F), -152.76 – -153.12 2,2',4,4',5,6'-hexafluoro-1,1'-biphenyl (26): Following
1
2
3
4
5
6
7
8
(m, 1F), -157.90 (t, J = 20.6 Hz, 1F), -160.75 – -161.06 (m,
2F). 13C{1H}NMR: (101 MHz, Chloroform-d) δ 151.5 (ddd, J
= 251.5, 10.1, 4.2 Hz), 144.2 (dddt, J = 249.7, 10.9, 7.3, 4.0
Hz), 141.3 (dtt, J = 256.3, 13.4, 5.1 Hz), 140.6 (dt, J = 255.9,
15.1 Hz), 139.7 – 136.6 (m), 122.2 (dddd, J = 8.5, 7.1, 5.2,
1.7 Hz), 115.3 – 114.8 (m), 113.2 (tdd, J = 16.5, 3.6, 1.7 Hz).
FTIR (ATR): see Supporting Information. MS (EI+): calc´d
for C12H2F8 [M]+: 298.0; found 297.9. EA: Anal. Calcd for
C12H2F8: C, 48.34; H, 0.68; N, 0.00; found C, 48.34; H; 0.46;
N, 0.00. Rf: 0.9 (pentane).
the general procedure with 1,3,5-trifluoro-2-iodobenzene,
(3,4,5-trifluorophenyl)boronic acid and RuPhos as phos-
phine ligand. The reaction was done on a 0.39 mmol scale.
The desired product was obtained as white solid (51 mg,
51%). Alternative Procedure: Following the general
procedure with 5,5-dimethyl-2-(2,4,5-trifluorophenyl)-
1,3,2-dioxaborinane and RuPhos as phosphine ligand. The
desired product was obtained as white solid (82 mg, 81%).
1H NMR: (400 MHz, Chloroform-d) δ 7.19 (ddd, J = 10.3,
8.7, 6.4 Hz, 1H), 7.06 (ddd, J = 10.2, 8.9, 6.6 Hz, 1H), 6.84 –
6.74 (m, 2H). 13C{1H}NMR: (101 MHz, Chloroform-d) δ
163.0 (dt, J = 251.9, 15.6 Hz), 160.4 (ddd, J = 251.4, 15.0,
9.4 Hz), 155.4 (ddd, J = 248.9, 9.5, 2.2 Hz), 150.6 (ddd, J =
253.7, 13.9, 12.0 Hz), 146.7 (ddd, J = 245.7, 12.5, 3.7 Hz),
119.9 (dd, J = 19.9, 4.0 Hz), 112.3 (dt, J = 18.6, 5.6 Hz),
107.4 (td, J = 20.0, 4.7 Hz), 106.0 (dd, J = 28.2, 21.0 Hz),
101.1 – 100.1 (m). 19F{1H}NMR: (235 MHz, Chloroform-d)
δ -106.33 (t, J = 6.9 Hz), -109.05 (dd, J = 10.8, 6.9 Hz), -
114.09 (dtd, J = 14.6, 10.8, 5.0 Hz), -131.81 (dd, J = 21.5, 5.0
Hz), -142.46 (dd, J = 21.5, 14.6 Hz). FTIR (ATR): see Sup-
porting Information. MS (EI+): calc´d for C12H4F6 [M]+:
262.0; found 261.9. EA: Anal. Calcd for C12H4F6: C, 54.98; H,
1,54; N, 0.00; found C, 54.97; H; 1.22; N, 0.00 Rf: 0.9 (pen-
tane).
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
2,2',3,4,4',5,5',6-octafluoro-1,1'-biphenyl (23): Follow-
ing the general procedure with pentafluoroiodobenzene,
(2,4,5-trifluorophenyl)boronic acid and RuPhos as phos-
phine ligand. The reaction was done on a 0.34 mmol scale.
The desired product was obtained as white solid (54,6 mg,
37%) in
a mixture with 2,2',4,4',5,5'-hexafluoro-1,1'-
1
biphenyl (30; 29%). H NMR: (400 MHz, Chloroform-d) δ
7.17 – 7.09 (m, 1H), 7.04 (ddd, J = 10.0, 8.8, 6.5 Hz, 1H).
13C{1H}NMR: (101 MHz, Chloroform-d) δ 155.4 (ddd, J =
250.3, 9.5, 2.4 Hz), 151.2 (ddd, J = 255.4, 14.3, 12.3 Hz),
148.3 – 145.5 (m), 145.7 – 142.95 (m), 143.03 – 140.01
(m), 139.5 – 136.2 (m), 119.7 (d, J = 21.1 Hz), 110.2 (d, J =
18.6 Hz), 108.3 (td, J = 18.3, 4.1 Hz), 106.5 (dd, J = 28.0,
21.2 Hz). 19F{1H}NMR: (235 MHz, Chloroform-d) δ -
113.29 – -113.94 (m), -129.75 (dd, J = 21.4, 5.5 Hz), -
139.88 – -140.40 (m), -141.36 (dd, J = 21.5, 14.5 Hz), -
152.58 (tt, J = 20.8, 2.2 Hz), -160.97 – -161.76 (m). MS
(EI+): calc´d for C12H2F8 [M]+: 298.0; found 297.9. Rf: 0.9
(pentane).
2,2',3,4,4',5,6'-heptafluoro-1,1'-biphenyl (27): Follow-
ing the general procedure with 1,3,5-trifluoro-2-
iodobenzene, 5,5-dimethyl-2-(2,3,4,5-tetrafluorophenyl)-
1,3,2-dioxaborinane (19) and DavePhos as phosphine
ligand. The reaction was done on a 0.39 mmol scale. The
desired product was obtained as white solid (73 mg, 67%).
1H NMR: (400 MHz, Chloroform-d) δ 7.04 – 6.95 (m, 1H),
6.86 – 6.76 (m, 2H). 13C{1H}NMR: (101 MHz, Chloroform-
d) δ 163.5 (dt, J = 252.2, 15.1 Hz), 160.5 (ddd, J = 252.2,
14.8, 8.9 Hz), 148.5 – 145.7 (m), 147.2 – 144.2 (m), 142.9 –
139.3 (m), 113.4 (d, J = 20.1 Hz), 112.6 (ddd, J = 14.6, 8.3,
4.4 Hz), 106.6 (t, J = 20.1 Hz), 101.8 – 100.3 (m).
19F{1H}NMR: (235 MHz, Chloroform-d) δ -105.3 (t, J = 7.1
Hz), -108.9 (dd, J = 10.6, 7.0 Hz), -137.1 – -137.5 (m), -
139.3 (ddd, J = 20.9, 12.0, 2.9 Hz), -154.1 (td, J = 20.3, 4.8
Hz), -154.9 (td, J = 20.2, 2.9 Hz). FTIR (ATR): see Support-
ing Information. MS (EI+): calc´d for C12H3F7 [M]+: 280.0;
found 279.9. EA: Anal. Calcd for C12H3F7: C, 51.45; H, 1.08;
N, 0.00; found C, 51.54; H; 0.81; 0.00, Rf: 0.9 (pentane).
2,2',3,3',4,4',5,5',6-nonafluoro-1,1'-biphenyl (24): Fol-
lowing the general procedure with pentafluoroiodoben-
zene,
5,5-dimethyl-2-(2,3,4,5-tetrafluorophenyl)-1,3,2-
dioxaborinane (19) and DavePhos as phosphine ligand.
The reaction was done on a 0.36 mmol scale. The desired
product was obtained as white solid (27.4 mg, 33%). The
product contained 33% of the corresponding homocou-
pling product. 19F{1H}NMR: (377 MHz, Chloroform-d) δ -
136.54 (dddd, J = 22.6, 20.9, 10.7, 5.6 Hz), -137.95 (ddd, J =
21.2, 12.0, 3.2 Hz), -139.76 (dddd, J = 23.2, 9.5, 6.7, 3.1 Hz),
-151.35 (tt, J = 20.7, 2.4 Hz), -151.81 (td, J = 20.5, 5.5 Hz), -
153.45 (td, J = 20.1, 3.4 Hz), -160.56 – -160.76 (m). MS
(EI+): calc´d for C12H1F9 [M]+: 316.0; found 315.9. Rf: 0.9
(pentane).
2,3,3',4,4',5',6-heptafluoro-1,1'-biphenyl (28): Follow-
ing the general procedure with 1,2,3,5-Tetrafluoro-4-
iodobenzene, (3,4,5-trifluorophenyl)boronic acid (2) and
CyJohnPhos as phosphine ligand. The reaction was done on
a 0.36 mmol scale. The desired product was obtained as
white solid (74.7 mg, 77%). The product contained <2 % of
the corresponding homocoupling Product. 1H NMR: (400
MHz, Chloroform-d) δ 7.09 (ddd, J = 7.5, 6.4, 1.3 Hz, 2H),
6.91 (tdd, J = 9.8, 6.1, 2.5 Hz, 1H). 13C{1H}NMR: (101 MHz,
Chloroform-d) δ 156.1 – 153.1 (m), 151.7 (ddd, J = 250.8,
10.1, 4.3 Hz), 152.5 – 149.4 (m), 150.8 – 147.5 (m), 140.6
(dt, J = 254.6, 15.1 Hz), 139.6 – 136.5 (m), 123.8 – 123.4
(m), 115.6 – 114.9 (m), 114.0 – 113.4 (m), 101.9 (ddd, J =
28.6, 21.4, 3.9 Hz). 19F{1H}NMR: (377 MHz, Chloroform-d)
δ -117.81 (dd, J = 11.1, 2.2 Hz, 1F), -130.78 (ddd, J = 21.7,
6.4, 2.4 Hz, 1F), -133.65 (d, J = 20.5 Hz, 2F), -135.04 (dd, J =
21.3, 6.3 Hz, 1F), -158.96 (t, J = 20.6 Hz, 1F), -163.61 (ddd, J
2,3',4,4',5',6-hexafluoro-1,1'-biphenyl (25): Following
the general procedure with 1,3,5-trifluoro-2-iodobenzene,
(3,4,5-trifluorophenyl)boronic acid (2) and CyJohnPhos as
phosphine ligand. The reaction was done on a 0.39 mmol
scale. The desired product was obtained as white solid
(101 mg, 99%). 1H NMR: (400 MHz, Chloroform-d) δ 7.01 –
6.95 (m, 2H), 6.75 – 6.62 (m, 2H). 13C{1H}NMR: (101 MHz,
Chloroform-d) δ 164.5 – 161.4 (m), 160.6 (ddd, J = 250.9,
14.7, 8.9 Hz), 151.6 (ddd, J = 249.7, 10.0, 4.2 Hz), 140.3 (dt,
J = 253.8, 15.1 Hz), 124.6 (td, J = 9.0, 5.1 Hz), 115.5 – 114.9
(m), 112.8 (td, J = 19.5, 3.6 Hz), 102.0 – 100.8 (m).
19F{1H}NMR: (235 MHz, Chloroform-d) δ -106.69 (t, J = 6.5
Hz), -111.16 (d, J = 6.6 Hz), -134.42 (d, J = 20.5 Hz), -160.14
(t, J = 20.5 Hz). FTIR (ATR): see Supporting Information.
MS (EI+): calc´d for C12H4F6 [M]+: 262.0; found 261.9. EA:
Anal. Calcd for C12H4F6: C, 54.98; H, 1.54; N, 0.00; found C,
55.01; H; 1.29; N, 0.00 Rf: 0.9 (pentane).
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Page 12 of 17
= 21.2, 10.9 Hz, 1F). FTIR (ATR): see Supporting Infor-
0.36 mmol scale. The desired product was obtained as
mation. MS (EI+): calc´d for C12H3F7 [M]+: 278.0; found
279.9. EA: Anal. Calcd for C12H3F7: C, 51.45; H, 1.08; N, 0.00;
found C, 51.56; H; 1.25; N, 0.00. Rf: 0.9 (pentane).
white solid (86.5 mg, 95%). The product contained <2 % of
the corresponding homocoupling product. 1H NMR: (250
MHz, Chloroform-d) δ 7.21 – 7.00 (m, 1H). 13C{1H}NMR:
(101 MHz, Chloroform-d) δ 152.7 – 149.7 (m), 150.1 –
147.3 (m), 140.4 (dt, J = 252.6, 15.6 Hz), 139.8 (dt, J =
253.9, 15.2 Hz), 124.1 – 123.7 (m), 123.5 (dt, J = 7.6, 3.7
Hz), 113.2 (ddd, J = 16.3, 6.5, 3.3 Hz), 112.7 (dd, J = 17.6,
4.1 Hz). 19F{1H}NMR: (235 MHz, Chloroform-d) δ -133.2
(dd, J = 20.4, 8.0 Hz), -133.6 (d, J = 20.6 Hz), -138.2 (dd, J =
20.2, 8.0 Hz), -158.8 (t, J = 20.3 Hz), -160.3 (t, J = 20.6 Hz).
FTIR (ATR): see Supporting Information. MS (EI+): calc´d
for C12H2F8 [M]+: 262.0; found 261.9. EA: Anal. Calcd for
C12H2F8: C, 54.98; H, 1.54; N, 0.00; found C, 54.59; H; 1.38;
N, 0.00. Rf: 0.9 (pentane).
1
2
3
4
5
6
7
8
3,3',4,4',5,5'-hexafluoro-1,1'-biphenyl (4): Following the
general procedure with 3,4,5-trifluoro-1-bromobenzene,
(3,4,5-trifluorophenyl)boronic acid (2) and CyJohnPhos as
phosphine ligand. The reaction was done on a 0.36 mmol
scale. The reaction was done on a 0.36 mmol scale. The
desired product was obtained as white solid (75.8 mg,
83%). 1H NMR: (400 MHz, Chloroform-d) δ 7.22 – 6.96 (m,
4H). 13C{1H}NMR: (101 MHz, Chloroform-d) δ 151.6 (ddd, J
= 251.2, 10.1, 4.3 Hz), 139.9 (dt, J = 254.1, 15.3 Hz), 134.6 –
134.0 (m), 111.4 – 110.8 (m). 19F{1H}NMR: (377 MHz,
Chloroform-d) δ -132.75 (d, J = 20.7 Hz), -160.30 (t, J = 20.4
Hz FTIR (ATR): see Supporting Information. MS (EI+):
calc´d for C12H4F6 [M]+: 262.0; found 261.9. EA: Anal. Calcd
for C12H4F6: C, 54.98; H, 1.54; N, 0.00; found C, 55.29; H;
1.51; N, 0.00. Rf: 0.9 (pentane).
9
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12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
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45
46
47
48
49
50
51
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53
54
55
56
57
58
59
60
2,2',3,4,4',5'-hexafluoro-1,1'-biphenyl (32): Following
the
general
procedure
with
1-bromo-2,3,4-
trifluorobenzene, 5,5-dimethyl-2-(2,4,5-trifluorophenyl)-
1,3,2-dioxaborinane (17) and RuPhos as phosphine ligand.
The reaction was done on a 0.47 mmol scale. The desired
product was obtained as white solid (96 mg, 77%). 1H
NMR: (400 MHz, Chloroform-d) δ 7.25 – 7.14 (m, 1H), 7.13
– 7.01 (m, 3H). 13C{1H}NMR: (101 MHz, Chloroform-d) δ
155.1 (ddd, J = 248.7, 9.4, 2.5 Hz), 151.6 (ddd, J = 242.8,
10.1, 3.2 Hz), 150.5 (ddd, J = 253.7, 14.4, 12.6 Hz), 150.5 –
147.7 (m), 147.0 (ddd, J = 246.1, 12.8, 3.9 Hz), 140.5 (dt, J =
252.1, 15.2 Hz), 125.1 – 124.8 (m), 119.6 – 119.4 (m),
119.4 – 119.0 (m), 118.3 – 117.9 (m), 112.5 (dd, J = 17.5,
4.0 Hz), 106.3 (dd, J = 28.4, 21.2 Hz). 19F{1H}NMR: (235
MHz, Chloroform-d) δ -115.95 (ddd, J = 16.3, 14.9, 4.8 Hz),
-132.28 (dd, J = 21.5, 4.8 Hz), -133.21 (dd, J = 20.5, 8.3 Hz),
-134.70 (ddd, J = 20.4, 16.3, 8.3 Hz), -142.17 (dd, J = 21.5,
14.9 Hz), -159.40 (t, J = 20.4 Hz). FTIR (ATR): see Support-
ing Information. MS (EI+): calc´d for C12H4F6 [M]+: 262.0;
found 261.9. EA: Anal. Calcd for C12H4F6: C, 54.98; H, 1.54;
N, 0.00; found C, 55.08; H; 1.05; N, 0.00 Rf: 0.9 (pentane).
2,3',4,4',5,5'-hexafluoro-1,1'-biphenyl (29): Following
the
general
procedure
with
1-bromo-2,4,5-
trifluorobenzene, (3,4,5-trifluorophenyl)boronic acid (2)
and CyJohnPhos as phosphine ligand. The reaction was
done on a 0.47 mmol scale. The desired product was ob-
tained as white solid (89 mg, 72%). 1H NMR: (400 MHz,
Chloroform-d) δ 7.19 (ddd, J = 10.3, 8.7, 6.4 Hz, 1H), 7.06
(ddd,
J = 10.2, 8.9, 6.6 Hz, 1H), 6.84 – 6.74 (m,
2H).13C{1H}NMR: (101 MHz, Chloroform-d) δ 154.6 (ddd, J
= 248.6, 9.2, 2.6 Hz), 151.2 (ddd, J = 250.8, 10.1, 4.3 Hz),
150.0 (ddd, J = 253.8, 14.1, 12.5 Hz), 147.1 (ddd, J = 246.4,
12.8, 3.8 Hz), 139.7 (dt, J = 253.8, 15.0 Hz), 129.7 (dd, J =
7.8 Hz), 122.4 (d, J = 14.9 Hz), 117.8 (dd, J = 20.1, 4.2 Hz),
113.4 – 112.9 (m), 106.53 (dd, J = 28.8, 21.0 Hz).
19F{1H}NMR: (235 MHz, Chloroform-d) δ -118.89 (dd, J =
15.3, 4.5 Hz), -132.60 (dd, J = 21.6, 4.4 Hz), -133.68 (dd, J =
20.5, 1.5 Hz), -141.60 (dd, J = 21.5, 15.1), -160.36 (t, J =
20.5). FTIR (ATR): see Supporting Information. MS (EI+):
calc´d for C12H4F6 [M]+: 262.0; found 261.9. EA: Anal. Calcd
for C12H4F6: C, 54.98; H, 1.54; N, 0.00; found C, 54.90; H;
1.15; N, 0.00 Rf: 0.9 (pentane).
3,3',4,5,5'-pentafluoro-4'-(trifluoromethyl)-1,1'-
biphenyl (33): Following the general procedure with 5-
bromo-1,3-difluoro-2-(trifluoromethyl)benzene,
(3,4,5-
trifluorophenyl)boronic acid (2) and CyJohnPhos as phos-
phine ligand. The reaction was done on a 0.38 mmol scale.
The desired product was obtained as colorless oil (99 mg,
83%). 1H NMR: (400 MHz, Chloroform-d) δ 7.20 (dd, J =
8.1, 6.4 Hz, 1H), 7.16 (d, J = 10.1 Hz, 1H). 13C{1H}NMR:
(101 MHz, Chloroform-d) δ 160.5 (dd, J = 259.7, 5.8 Hz),
151.9 (ddd, J = 252.0, 10.1, 4.2 Hz), 144.5 (t, J = 10.9 Hz),
140.7 (dt, J = 255.6, 15.3 Hz), 133.6 , 121.7 (q, J = 274.1 Hz),
111.8 – 111.4 (m), 111.4 – 111.0 (m), 108.4 – 107.0 (m).
19F{1H}NMR: (235 MHz, Chloroform-d) δ -56.54 (t, J = 21.8
Hz), -109.22 (q, J = 21.9 Hz), -132.25 (d, J = 20.7 Hz), -
158.58 (t, J = 20.2 Hz). FTIR (ATR): see Supporting Infor-
mation. MS (EI+): calc´d for C13H4F8 [M]+: (312.0); found
(311.9). EA: Anal. Calcd for C13H4F8: C, 50.02; H, 1.29; N,
0.00; found C, 49.80; H; 1.03; N, 0.02 Rf: 0,1 (pentane).
2,2',4,4',5,5'-hexafluoro-1,1'-biphenyl (30): Following
the
general
procedure
with
1-bromo-2,4,5-
trifluorobenzene, 5,5-dimethyl-2-(2,4,5-trifluorophenyl)-
1,3,2-dioxaborinane (17) and RuPhos as phosphine ligand.
The reaction was done on a 0.47 mmol scale. The desired
product was obtained as white solid (90 mg, 73%). 1H
NMR: (400 MHz, Chloroform-d) δ 7.17 – 7.07 (m, 2H), 7.02
– 6.91 (m, 2H).13C{1H}NMR: (101 MHz, Chloroform-d) δ
155.1 (dd, J = 249.7, 9.6 Hz), 152.3 – 148.7 (m), 146.9 (ddd,
J = 245.8, 12.7, 2.7 Hz), 119.4 – 119.0 (m), 118.1 – 117.7
(m), 106.9 – 105.7 (m). 19F{1H}NMR: (235 MHz, Chloro-
form-d) δ -116.00 – -116.22 (m), -132.05 – -132.39 (m), -
141.87 – -142.35 (m). FTIR (ATR): see Supporting Infor-
mation. MS (EI+): calc´d for C12H4F6 [M]+: 262.0; found
261.9. EA: Anal. Calcd for C12H4F6: C, 54.98; H, 1.54; N, 0.00;
found C, 54.98; H; 1.13; N, 0.00 Rf: 0.9 (pentane).
4-(3,5-difluorophenyl)-2,3,5-trifluoropyridine
(34):
Following the general procedure with 2,3,5-trifluoro-4-
iodopyridine, 3,5-difluorophenyl boronic acid and XPhos
as phosphine ligand. The reaction was done on a 0.39
mmol scale. The desired product was obtained as white
solid (62 mg, 65%). The product also contained 2% of the
2,3,3',4,4',5'-hexafluoro-1,1'-biphenyl (31): Following
the
general
procedure
with
2,3,4-trifluoro-1-
bromobenzene, (3,4,5-trifluorophenyl)boronic acid (2)
and CyJohnPhos as phosphine ligand. The reaction was
done on a 0.36 mmol scale. The reaction was done on a
1
corresponding homocoupling product. H NMR: (400 MHz,
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The Journal of Organic Chemistry
Chloroform-d) δ 8.02 – 7.99 (m, 1H), 7.12 – 7.04 (m, 2H),
sponding homocoupling product.. 1H NMR: (400 MHz,
6.98 (tt, J = 8.8, 2.3 Hz, 1H). 13C{1H}NMR: (101 MHz, Chlo-
roform-d) δ 161.9 (dd, J = 250.2, 12.8 Hz), 152.5 (dd, J =
257.5, 4.3 Hz), 147.8 (ddd, J = 237.2, 15.2, 2.2 Hz), 145.8 (d,
J = 162.1 Hz), 141.0 (ddd, J = 267.0, 31.7, 2.8 Hz), 128.3 –
127.8 (m), 127.8 – 127.6 (m), 112.7 – 111.7 (m), 104.7 (t, J
= 25.0 Hz). 19F{1H}NMR: (377 MHz, Chloroform-d) δ -
88.00 (dd, J = 29.2, 25.3 Hz), -108.10 , -132.10 (dd, J = 29.0,
1.6 Hz), -139.92 (dd, J = 25.8, 1.9 Hz). FTIR (ATR): see
Supporting Information. MS (EI+): calc´d for C11H4F5N [M]+:
(245.0); found (244.9). EA: Anal. Calcd for C11H4F5N: C,
53.89; H, 1.64; N, 5.71; found C, 54.32; H; 3.84; N, 3.73 Rf:
0,1 (pentane).
Chloroform-d) δ 7.97 (dd, J = 2.2, 1.3 Hz, 1H), 7.06 – 6.94
(m, 1H). 13C{1H}NMR: (101 MHz, Chloroform-d) δ 152.6
(dd, J = 259.3, 4.1 Hz), 147.4 (ddd, J = 237.8, 14.8, 2.3 Hz),
146.2 (dddd, J = 249.5, 10.3, 3.6, 2.3 Hz), 144.4 (dddd, J =
253.1, 11.6, 3.7, 1.4 Hz), 142.5 – 139.4 (m), 142.9 – 139.6
(m), 140.4 (dddd, J = 255.9, 16.6, 12.4, 4.0 Hz), 127.9 (ddd,
J = 27.8, 14.3, 6.6 Hz), 120.6 (t, J = 16.5 Hz), 111.6 (ddd, J =
20.8, 4.1, 2.1 Hz), 109.2 (t, J = 7.6 Hz). 19F{1H}NMR(377
MHz, Chloroform-d) δ -87.45 (dd, J = 29.3, 25.3 Hz), -
129.71 (dd, J = 29.3, 12.0 Hz), -135.52 – -135.88 (m), -
136.48 (dd, J = 25.3, 12.7 Hz), -137.41 (ddd, J = 21.1, 12.2,
3.6 Hz), -150.66 (td, J = 20.4, 6.1 Hz), -153.04 (td, J = 20.0,
3.4 Hz). FTIR (ATR): see Supporting Information. MS (EI+):
calc´d for C11H2F7N [M]+: (281.0); found (280.9). EA: Anal.
Calcd for C11H2F7N: C, 47.00; H, 0.72; N, 4.98; found C,
45.56; H; 2.33; N, 4.34 Rf: 0,1 (pentane).
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
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29
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31
32
33
34
35
36
37
38
39
40
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48
49
50
51
52
53
54
55
56
57
58
59
60
2,3,5-trifluoro-4-(3,4,5-trifluorophenyl)pyridine (35):
Following the general procedure with 2,3,5-trifluoro-4-
iodopyridine, 3,4,5-trifluorophenyl boronic acid and
CyJohnPhos as phosphine ligand. The reaction was done on
a 0.39 mmol scale. The desired product was obtained as
white solid. (85 mg, 84%). 1H NMR: (400 MHz,
Chloroform-d) δ 7.94 (t, J = 1.8 Hz, 1H), 7.18 – 7.10 (m, 2H).
13C{1H}NMR: (101 MHz, Chloroform-d) δ 154.9 – 152.1
(m), 151.5 (ddd, J = 251.9, 10.2, 4.1 Hz), 150.3 – 147.6 (m),
142.1 (ddd, J = 266.8, 31.7, 2.2 Hz), 141.0 (dt, J = 257.1,
15.0 Hz), 129.2 (ddd, J = 28.8, 14.3, 6.6 Hz), 126.8 (t, J =
4-(3,5-difluorophenyl)-2,3,5,6-tetrafluoropyridine
(38): Following the general procedure with 2,3,5,6-
Tetrafluoro-4-iodopyridine, (3,5-difluorophenyl) boronic
acid and XPhos as phosphine ligand. The reaction was
done on a 0.36 mmol scale. The desired product was ob-
tained as white solid (77 mg, 72%). The product mixture
contained 12% of the corresponding homocoupling prod-
uct (3,3',5,5'-tetrafluoro-1,1'-biphenyl). 1H NMR: (400
MHz, Chloroform-d) δ 7.11 – 7.08 (m, 1H), 7.01 (tt, J = 8.7,
2.3 Hz, 1H). 13C{1H}NMR: (101 MHz, Chloroform-d) δ 163.0
(dd, J = 250.9, 12.7 Hz), 144.0 (dddd, J = 246.2, 16.6, 13.0,
3.0 Hz), 140.6 – 137.4 (m), 131.2 – 130.5 (m), 128.3 (t, J =
10.6 Hz), 113.4 – 113.0 (m), 106.3 (t, J = 25.0 Hz).
19F{1H}NMR: (377 MHz, Chloroform-d) δ -89.34 – -89.57
(m), -107.57 , -144.18 – -144.40 (m). FTIR (ATR): see Sup-
porting Information. MS (EI+): calc´d for C11H3F6N [M]+:
(263.0); found (262.9). EA: Anal. Calcd for C11H3F6N: C,
50.21; H, 1.15; N, 5.32; found C, 51.47; H; 1.338; N, 4.54 Rf:
0,4 (pentane).
13.9 Hz), 122.2
– 121.6 (m), 115.4 – 114.4 (m).
19F{1H}NMR: (377 MHz, Chloroform-d) δ -87.68 (dd, J =
29.3, 25.5 Hz), -132.35 (dd, J = 29.0, 1.4 Hz), -132.47 (d, J =
20.5 Hz), -140.16 (d, J = 25.1 Hz), -156.38 (t, J = 20.4 Hz).
FTIR (ATR): see Supporting Information. MS (EI+): calc´d
for C11H3F6N [M]+: (263.0); found (262.9). EA: Anal. Calcd
for C11H3F6N: C, 50.21; H, 1.15; N, 5.32; found C, 49.73; H;
2.28; N, 4.50 Rf: 0,7 (pentane).
2,3,5-trifluoro-4-(2,3,4-trifluorophenyl)pyridine (36):
Following the general procedure with 2,3,5-trifluoro-4-
iodopyridine, 2,3,4-trifluorophenyl boronic acid and
CyJohnPhos as phosphine ligand. The reaction was done on
a 0.39 mmol scale. The desired product was obtained as
colorless oil (72 mg, 72%%). The product also contained
2,3,5,6-Tetrafluoro-4-(3,4,5-trifluorophenyl)pyridine
(39): Following the general procedure with 2,3,5,6-
Tetrafluoro-4-iodopyridine, (3,4,5-trifluorophenyl)boronic
acid and CyJohnPhos as phosphine ligand. The reaction
was done on a 0.36 mmol scale. The desired product was
obtained as colorless oil (98 mg, 98%). The product also
contained 2% of the corresponding homocoupling product.
1H NMR: (400 MHz, Chloroform-d) δ 7.18 – 7.11 (m, 2H).
13C{1H}NMR: (101 MHz, Chloroform-d) δ 151.7 (ddd, J =
252.8, 10.1, 4.1 Hz), 144.2 (dddd, J = 246.4, 16.8, 12.8, 3.0
Hz), 141.3 (dt, J = 258.1, 14.9 Hz), 140.8 – 137.6 (m), 130.3
(t, J = 14.1 Hz), 121.7 – 121.3 (m), 115.2 – 114.7
(m).19F{1H}NMR: (377 MHz, Chloroform-d) δ -89.04 – -
89.27 (m), -131.96 (d, J = 20.4 Hz), -144.43 – -144.68 (m), -
155.48 (t, J = 20.5 Hz). FTIR (ATR): see Supporting Infor-
mation. MS (EI+): calc´d for C11H2F7N [M]+: (281.0); found
(280.9). EA: Anal. Calcd for C11H2F7N: C, 47.00; H, 0.72; N,
4.98; found C, 46.84; H; 0.91; N, 4.88 Rf: 0,3 (pentane).
1
2% of the corresponding homocoupling product.. H NMR:
(400 MHz, Chloroform-d) δ 8.01 (dd, J = 2.2, 1.3 Hz, 1H),
7.21 – 7.09 (m, 2H). 13C{1H}NMR: (101 MHz, Chloroform-d)
δ 154.0 (dd, J = 258.4, 4.2 Hz), 152.7 (ddd, J = 254.9, 9.9, 3.3
Hz), 149.4 (ddd, J = 256.1, 11.2, 3.7 Hz), 148.6 (ddd, J =
237.3, 14.9, 2.3 Hz), 142.5 (ddd, J = 267.8, 31.8, 2.7 Hz),
140.7 (dt, J = 253.9, 15.2 Hz), 128.9 (ddd, J = 28.0, 14.3, 6.5
Hz), 125.6 – 125.1 (m), 123.1 – 122.4 (m), 113.09 (dd, J =
18.1, 3.8 Hz), 111.8 (dt, J = 12.9, 3.4 Hz). 19F{1H}NMR: (377
MHz, Chloroform-d) δ -88.08 (dd, J = 29.1, 25.3 Hz), -
129.78 (dd, J = 20.5, 10.0 Hz), -129.95 (dd, J = 29.2, 12.2
Hz), -130.95 – -131.42 (m), -136.97 (dd, J = 25.2, 12.2 Hz), -
158.20 (t, J = 20.4 Hz). FTIR (ATR): see Supporting Infor-
mation. MS (EI+): calc´d for C11H3F6N [M]+: (263.0); found
(262.9). EA: Anal. Calcd for C11H3F6N: C, 50.21; H, 1.15; N,
5.32; found C, 48.07; H; 1.94; N, 5.09 Rf: 0,1 (pentane).
2,3,5-trifluoro-4-(2,3,4,5-tetrafluorophenyl)pyridine
(37): Following the general procedure with 2,3,5-trifluoro-
Large Scale Procedure (36 mmol) for Suzuki-Miyaura
coupling of 2,3,3',4',5,5',6-Heptafluoro-1,1'-biphenyl
(3). An argon-purged 500 ml Schlenk-flask was charged
with THF (100 ml) and toluene (100 ml) and deoxygenated
via the freeze-pump-thaw technique. Afterwards 1.91 g
CyJohnPhos (5.4 mmol, 15 mol%) and 1.66 g Pd2(dba)3 (1.8
mmol, 5 mol%) were added. The solution was stirred at 50
4-iodopyridine,
5,5-dimethyl-2-(2,3,4,5-
tetrafluorophenyl)-1,3,2-dioxaborinane and DavePhos as
phosphine ligand. The reaction was done on a 0.39 mmol
scale. The desired product was obtained as yellow oil7 (39
mg, 36%) The product also contained <1% of the corre-
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Page 14 of 17
°C for 2 h to prepare the active catalyst. During that time,
the color of the mixture changed from dark red to dark
orange. Subsequently 33 ml ddH2O, 10.02 K2CO3
(72,5 mmol, 200 mol%), 10.00 g 1,2,4,5-tetrafluoro-3-
iodobenzene (36 mol) and 6.37 3,4,5-
mation. MS (EI+): calc´d for C6HF4I [M]+: 275.9; found
275.9. b.p.: 59°C (15 mbar)
1
2
3
4
5
6
7
8
g
2,3,5-trifluoro-4-iodopyridine (41): A flame-dried, two-
necked 250 ml Schlenk-flask was filled with 50 ml dry THF
and cooled to -78°C. 7.5 ml n-BiLi (2.5 M in hexanes, 18.8
mmol) and 2.65 ml (18.8 mmol) diiosopropylamine were
added to the solvent. The mixture was stirred for 15 min.
Subsequently 1.8 ml 2,3,5-trifluoropyridine (18.8 mmol)
was added dropwise within 30 min with a syringe pump.
After the addition was completed, the mixture was stirred
for additional 2.5 h. In a second flame-dried Schlenk-flask
under an argon atmosphere 4.77 g I2 (18.8 mmol) was
dissolved in 50 ml dry THF. The resulting solution is trans-
ferred to the reaction mixture via cannula under a positive
pressure of argon, stirred for an additional 10 min and
warmed to room temperature overnight. The reaction
mixture was quenched with H2O and the organic phase
was washed with saturated Na2S2O3. The organic phase
was dried with anhydrous Na2SO4 and the organic solvents
were evaporated for the most part. After fractional distilla-
tion, the product was obtained as very white crystalline
g
trifluorophenylboronic acid (36 mmol) were added. The
flasked was equipped with a reflux condenser, septum and
an argon filled balloon and the biphasic mixture was re-
fluxed at 95 °C for 60 h. After cooling to room tempera-
ture, the aqueous phase was separated and the organic
phase was removed in vacuo. The residue is resuspended
with pentane and silica is added to the mixture. The sol-
vents are removed in vacuo. This should be done with care
due to the volatile nature of the corresponding products.
The residue is filtered through a plug of silica with pentane
as eluent. The pentane was removed in vacuo and the
product was obtained as white solid (10.06 g, 35.7 mmol,
99% yield).
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1,2,4,5-tetrafluoro-3-iodobenzene (1): A flame-dried,
two-necked 500 ml Schlenk-flask, equipped with an inner
thermometer was filled with 200 ml dry DEE and 11.2 ml
1,2,4,5-tetrafluorobenzene (15.0 g, 100 mmol) under an
argon atmosphere. The solution was cooled to -78 °C and
40 ml n-BuLi (2,5 M in hexanes) was added dropwise with
a syringe pump at a rate of 40 ml/h. It is important that the
temperature of the reaction mixture does not exceed -40
°C due to the otherwise occurring LiF formation. After the
addition is completed, the mixture is stirred for additional
2 h. In a second flame-dried Schlenk-flask under an argon
atmosphere 25.3 g I2 is dissolved in 100 ml dry THF. The
resulting solution is transferred to the reaction mixture via
cannula under a positive pressure of argon, stirred for an
additional 10 min and warmed to room temperature over-
night. The reaction mixture was quenched with H2O and
the organic phase was washed with saturated Na2S2O3. The
organic phase was dried with MgSO4 and the organic sol-
vents were evaporated for the most part. After fractional
distillation, the product was obtained as very light pink
liquid (20.0 g 72,5 %). 1H NMR: (250 MHz, Chloroform-d) δ
7.16 (tt, J = 9.5, 7.2 Hz, 1H). 13C{1H}NMR: (63 MHz, Chloro-
form-d) δ 147.1 (ddt, J = 245.1, 14.9, 4.1 Hz), 147.9 – 143.0
(m), 106.7 (t, J = 22.9 Hz), 73.4 (t, J = 27.3 Hz).
19F{1H}NMR: (235 MHz, Chloroform-d) δ -119.73 – -
120.76 (m, 2F), -136.20 – -137.61 (m, 2F). FTIR (ATR): see
Supporting Information. MS (EI+): calc´d for C6HF4I [M]+:
275.9; found 275.9. b.p.: 56 °C (12 mbar).
1
solid (2.62 g, 53.85%). H NMR: (250 MHz, Chloroform-d)
δ 7.83 – 7.79 (m, 1H). 13C{1H}NMR: (101 MHz, Chloroform-
d) δ 157.7 (ddd, J = 254.9, 4.4, 1.7 Hz), 147.4 (ddd, J =
239.5, 16.4, 2.3 Hz), 146.6 (ddd, J = 263.4, 32.1, 2.3 Hz),
127.7 (ddd, J = 29.5, 14.4, 6.2 Hz), 85.8 (ddd, J = 28.8, 23.3,
3.0 Hz). 19F{1H}NMR: (235 MHz, Chloroform-d) δ -87.89 (t,
J = 26.4 Hz), -111.85 (d, J = 27.2 Hz), -116.94 (d, J = 24.7
Hz). FTIR (ATR): see Supporting Information. MS (EI+):
calc´d for C5H1F3IN [M]+: (258.9); found (258.9). EA: Anal.
Calcd for C5H1F3IN: C, 23.19; H, 0.39; N, 5.41; found C, 23.0;
H; 0.45; N, 5.41.
2,3,5,6-tetrafluoro-4-iodopyridine (42): This compound
was
synthesized
analogous
to
2,3,5-trifluoro-4-
iodopyridine (41) described above with 2,3,5,6-pyridine as
starting material. The reaction was performed on a
6.6 mmol scale. The desired product was obtained as off-
white solid (760 mg, 41%). 13C{1H}NMR: (63 MHz, Chlo-
roform-d) δ 146.0 – 141.0 (m), 145.1 – 140.2 (m), 88.6
(tt, J = 25.8, 2.3 Hz). 19F{1H}NMR: (235 MHz, Chloro-
form-d) δ -89.38 (dq, J = 28.0, 12.9 Hz), -122.33 – -
123.18 (m). FTIR (ATR): see Supporting Information. MS
(EI+): calc´d for C5F4IN [M]+: (276.9); found (276.9). EA:
Anal. Calcd for C5F4IN: C, 21.68; H, 0.00; N, 5.06; found C,
20.54; H; 0.13; N, 4.83.
(2,4,5-trifluorophenyl)boronic acid (6): A flame-dried,
500 ml Schlenk-flask, equipped charged with 200 ml dry
DEE and 5.54 ml 2,4,5-trifluorobromobenzene (10 g, 47.4
mmol) under an argon atmosphere. The solution was
cooled to -78 °C and 18 ml n-BuLi (2,5 M in hexanes) was
added dropwise within. It is important that the tempera-
ture of the reaction mixture does not exceed -40 °C due to
the otherwise occurring LiF formation. After the addition is
completed, the mixture is stirred for an additional hour.
B(OMe)3 is added and the mixture is stirred for an addi-
tional 10 min and warmed to room temperature overnight.
The reaction mixture was quenched with 2M aq. HCl and
the mixture is stirred for 2 h. The aqueous phase is sepa-
rated and extracted twice with DEE. The combined organic
phases are washed with aq. sat. NaHCO3. The organic phase
is dried with anhydrous Na2SO4 and the organic solvents
1,2,3,5-tetrafluoro-4-iodobenzene(40): This compound
was synthesized analogous to 1,2,4,5-tetrafluoro-3-
iodobenzene (1) described above with 1,2,3,5-
tetrafluorobenzene as starting material. After fractional
distillation, the product was obtained as lightly pink liquid
(4.5 g, 49% yield). The product contains traces of the diio-
dinated side product (<2%). 1H NMR: (250 MHz, Chloro-
form-d) δ 7.12 – 6.67 (m, 1H). 13C{1H}NMR: (63 MHz, Chlo-
roform-d) δ 157.1 (dddd, J = 244.9, 12.4, 6.4, 3.8 Hz), 154.5
– 148.5 (m), 136.9 (dddd, J = 252.7, 17.5, 15.6, 5.5 Hz),
100.9 (ddd, J = 29.9, 22.1, 3.8 Hz), 66.0 (ddd, J = 31.7, 26.6,
5.0 Hz). 19F{1H}NMR: (235 MHz, Chloroform-d) δ -96.19
(d, J = 9.7 Hz, 1F), -111.72 (ddd, J = 22.3, 5.2, 2.6 Hz, 1F), -
131.07 (ddd, J = 20.4, 4.8, 2.4 Hz, 1F), -161.84 (ddd, J =
21.8, 21.3, 9.7 Hz, 1F). FTIR (ATR): see Supporting Infor-
ACS Paragon Plus Environment

Page 15 of 17
The Journal of Organic Chemistry
are removed in vacuo. The crude product was washed with acid (6) as starting material. The product was obtained as
a white solid (363 mg, 52% yield). 1H NMR: (250 MHz,
Chloroform-d) δ 7.50 (ddd, J = 10.7, 9.7, 5.5 Hz, 1H), 6.85
(ddd, J = 10.5, 8.7, 6.1 Hz, 1H), 3.78 (s, 4H), 1.03 (s, 6H).
13C{1H}NMR: (75 MHz, Chloroform-d) δ 162.5 (ddd, J =
249.6, 9.4, 2.1 Hz), 152.1 (ddd, J = 254.0, 14.5, 13.2 Hz),
146.9 (ddd, J = 244.1, 11.9, 3.6 Hz), 123.4 (ddd, J = 17.6,
10.3, 1.9 Hz), 105.6 (dd, J = 31.1, 19.9 Hz), 72.6 , 32.0 , 22.0
C-B missing. 19F{1H}NMR: (235 MHz, Chloroform-d) δ -
106.19 (ddd, J = 16.8, 6.9, 1.6 Hz, 1F), -130.14 (dd, J = 21.3,
6.9 Hz, 1F), -144.71 (dd, J = 21.3, 16.8 Hz, 1F). 11B NMR:
(80 MHz, Chloroform-d) δ 26.00. FTIR (ATR): see Support-
ing Information. MS (EI+): calc´d for C11H12BF3O2 [M]+:
244.1; found 244.1. EA: Anal. Calcd for C11H12BF3O2: C,
54.14; H, 4.87; N, 0.00; found C, 54.22; H; 4.87; N, 0.00. Rf:
0.4 (Cyclohexane/EtOAc 5:1)
1
2
3
4
5
6
7
8
pentane and dried. The product was obtained as white
solid (5.80 g, 70 % yield). H NMR: (250 MHz, Acetone-d6)
1
δ 7.59 (ddd, J = 11.0, 9.7, 5.5 Hz, 1H), 7.38 (d, J = 1.6 Hz,
2H), 7.16 (ddd, J = 10.9, 8.8, 6.1 Hz, 1H). 13C{1H}NMR: (63
MHz, Acetone-d6) δ 162.6 (dd, J = 244.7, 9.5 Hz), 151.8 (dt, J
= 251.6, 14.2 Hz), 147.0 (dd, J = 243.4, 10.5 Hz), 123.4 (dd,
J = 17.4, 10.8 Hz), 121.14 – 114.58 (m), 105.6 (dd, J = 32.1,
20.3 Hz). 19F{1H}NMR: (235 MHz, Acetone-d6) δ 69.66 (dd,
J = 17.0, 6.3 Hz), 44.75 (dd, J = 21.0, 6.4 Hz), 31.29 (dd, J =
18.9 Hz). FTIR (ATR): see Supporting Information. MS
(EI+): calc´d for C6H4BF3O2 [M]+: 276.0; found 276.0. EA:
Anal. Calcd for C6H4BF3O2: C, 40.97; H, 2.29; N, 0.00 found
C, 41.08; H; 2.26; N, 0.00.
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40
41
42
43
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45
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(2,3,4-trifluorophenyl)boronic acid (7): This compound
was
synthesized
analogous
to
(2,4,5-
trifluorophenyl)boronic acid (6) described above with
2,3,4-trifluorobromobenzene as starting material. The
product was obtained as white solid (3.65 g, 87 % yield).
1H NMR: (250 MHz, Acetone-d6) δ 7.52 (ddd, J = 8.8, 5.5,
2.4 Hz, 1H), 7.44 (d, J = 1.1 Hz, 2H), 7.16 (dddd, J = 10.4,
8.6, 6.6, 1.9 Hz, 1H). 13C{1H}NMR: (63 MHz, Acetone-d6) δ
156.5 (dd, J = 161.6, 6.1 Hz), 152.6 (dd, J = 163.1, 6.9 Hz),
140.2 (ddd, J = 248.5, 17.9, 14.7 Hz), 13010 (q, J = 8.2 Hz),
124.1 – 116.3 (m), 113.1 (d, J = 16.6 Hz). 19F{1H}NMR:
(235 MHz, Acetone-d6) δ 48.08 (dd, J = 21.0, 9.2 Hz, 1F),
42.72 (dd, J = 19.4, 9.0 Hz, 1F), 12.12 (t, J = 20.1 Hz). 11B
NMR (80 MHz, Acetone-d6) δ 27.50. FTIR (ATR): see Sup-
porting Information. MS (GC/MS; EI+): calc´d for C6H4BF3O2
[M]+: 276.0; found 276.0. EA: Anal. Calcd for C6H4BF3O2: C,
40.97; H, 2.29; N, 0.00; found C, 40.98; H; 1.93; N, 0.00.
5,5-dimethyl-2-(2,3,5,6-tetrafluorophenyl)-1,3,2-
dioxaborinane
(18):
With
(2,3,5,6-
tetrafluorophenyl)boronic acid (8) as starting material.
The product was obtained as a white solid (3.68 g, 54%
yield). 1H NMR: (250 MHz, Chloroform-d) δ 7.04 (tt, J = 9.6,
7.4 Hz, 1H), 3.82 (s, 4H), 1.07 (s, 6H). 13C{1H}NMR: (75
MHz, Chloroform-d) δ 147.9 (dddd, J = 245.8, 13.0, 11.1, 3.6
Hz), 145.6 (dddd, J = 248.3, 16.5, 8.8, 3.8 Hz), 114.9 – 110.7
(m), 107.2 (tt, J = 22.6, 1.6 Hz), 72.7 , 31.8 , 21.4.
19F{1H}NMR: (235 MHz, Chloroform-d) δ -133.33 (dd, J =
22.5, 14.7 Hz), -139.91 (dd, J = 22.4, 14.7 Hz). 11B NMR: (80
MHz, Chloroform-d) δ 25.88. FTIR (ATR): see Supporting
Information. MS (EI+): calc´d for C11H11BF4O2 [M]+: 262.1;
found 262.0. EA: Anal. Calcd for C11H11BF4O2: C, 50.43; H,
4.23; N, 0.00; found C, 49.95; H; 4.03; N, 0.00. Rf: 0.2 (Cy-
clohexane/EtOAc 5:1)
General Procedure for the Boresterfication. These
compounds were prepared according to a modified proce-
dure.13 In a 100 ml round bottom flask 5.7 mmol of the
corresponding boronic acid and 2.2 g 2,2-dimethyl-1,3-
propanediol (6.3 mmol, 110 mol%) were dissolved in 50
ml dry THF. 3.4 g MgSO4 (28.4 mmol, 500 mol%) was add-
ed and the suspension was stirred for 16 hours at room
temperature. The MgSO4 was filtered off and washed with
THF. The solvents of the filtrate were evaporated in vacuo.
The crude product was purified filtered through a plug of
silica (hexanes/DEE 1:1).
6-methyl-2-(2,3,4-trifluorophenyl)-1,3,6,2-
dioxazaborocane-4,8-dione (16): This molecule was
synthesized after a modified procedure of Burke and
coworkers.93 In 100 ml round bottom flask 1g 2,3,4-
trilfuoroboronic acid (7) and 920 mg Methyliminodiacetic
acid were dissolved in a mixture of 50 ml toluene and 5 ml
DMSO. The mixture was refluxed for 20 h in an Dean-Stark
apparatus. The solvents were removed in vacuo and the
residue was purified by column chromatography (hex-
ane/EtOAc 1:2). The product was obtained as white solid
(524 mg, 32% yield).
5,5-dimethyl-2-(2,3,4-trifluorophenyl)-1,3,2-
dioxaborinane (15): With (2,3,4-trifluorophenyl)boronic
acid (7) as starting material. The product was obtained as
a white solid (1.03 g, 72% yield). 1H NMR: (250 MHz, Chlo-
roform-d) δ 7.45 (dddd, J = 8.7, 6.3, 2.5 Hz, 1H), 7.29 (s,
0H), 6.95 (dddd, J = 9.5, 8.5, 6.4, 1.8 Hz, 0H), 3.82 (s, 1H),
1.07 (s, 1H). 13C{1H}NMR: (63 MHz, Acetone-d6) δ 156.5
(dd, J = 161.6, 6.1 Hz), 152.6 (dd, J = 163.1, 6.9 Hz), 140.2
(ddd, J = 248.5, 17.9, 14.7 Hz), 131.0 (q, J = 8.2 Hz), 124.1 –
1H NMR: (250 MHz, DMSO-d6) δ 7.39 – 7.20 (m, 2H), 4.43
(dd, J = 17.3, 0.9 Hz, 2H), 4.12 (d, J = 17.3 Hz, 2H), 2.65 (s,
3H). 13C{1H}NMR: (63 MHz, DMSO-d6) δ 169.3 , 153.8 (ddd,
J = 244.6, 8.7, 3.1 Hz), 151.6 (ddd, J = 248.5, 9.8, 3.6 Hz),
139.3 (ddd, J = 249.0, 18.1, 14.7 Hz), 129.5 – 129.0 (m),
113.2 (dd, J = 16.2, 3.3 Hz), 62.8 (d, J = 1.5 Hz), 48.0, C-B
missing. 19F{1H}NMR: (235 MHz, DMSO-d6) δ -128.90 (dd,
J = 23.0, 8.2 Hz), -134.33 (dd, J = 21.0, 8.2 Hz), -163.02 (dd,
J = 23.0, 20.9 Hz). 11B NMR: (80 MHz, DMSO-d6) δ 10.74.
FTIR (ATR): see Supporting Information. MS (EI+): calc´d
for C11H9BF3NO4 [M]+: 287.1; found 287.0. EA: Anal. Calcd
for C11H9BF3NO4: C, 46.03; H, 3.16; N, 4.88; found C, 46.14;
H; 3.23; N, 5.03.
116.3 (m), 113.1 (d,
J = 16.6 Hz), C-B missing.
19F{1H}NMR: (235 MHz, Chloroform-d) δ -127.11 (dd, J =
20.9, 10.5 Hz), -131.52 (dd, J = 19.9, 10.4 Hz), -162.44 (t, J =
20.4 Hz). FTIR (ATR): see Supporting Information. 11B
NMR: (80 MHz, Acetone-d6) δ 27.50. MS (EI+): calc´d for
C11H12BF3O2 [M]+: 244.1; found 244.1. EA: Anal. Calcd for
C11H12BF3O2: C, 54.14; H, 4.87; N, 0.00; found C, 54.14; H;
4.85; N, 0.00. Rf: 0.5 (Cyclohexane/EtOAc 5:1)
ASSOCIATED CONTENT
Supporting Information
This material is available free of charge via the Internet at ACS
Publication website at DOI: ….
5,5-dimethyl-2-(2,4,5-trifluorophenyl)-1,3,2-
dioxaborinane (17): With (2,4,5-trifluorophenyl)boronic
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 16 of 17
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3636-3638.
Milstein, D.; Stille, J. K., J. Am. Chem. Soc. 1978, 100,
Additional Screening Data and Spectroscopic Data
1
2
3
4
5
6
7
8
(PDF)
(23)
8978-8985.
(24)
10768-10771.
Casado, A. L.; Espinet, P., J. Am. Chem. Soc. 1998, 120,
AUTHOR INFORMATION
Corresponding Author
*stefan.m.huber@rub.de, david.bulfield@rub.de
Notes
The authors declare no competing financial interest.
Han, S.; Movassaghi, M., J. Am. Chem. Soc. 2011, 133,
(25)
Albeniz, A. C.; Casares, J. A., Advances in Organometallic
Chemistry, Vol 62 2014, 62, 1-110.
(26)
Espinet, P., Organometallics 2011, 30, 611-617.
(27)
Albeniz, A. C.; Espinet, P., Chem-Eur J 2008, 14, 10141-10148.
(28) Martinez-Arranz, S.; Carrera, N.; Albeniz, A. C.; Espinet,
P.; Vidal-Moya, A., Adv Synth Catal 2012, 354, 3551-3560.
(29) Li, Z.; Lu, J.; Tse, S.-C.; Zhou, J.; Du, X.; Tao, Y.; Ding, J., J.
Mater. Chem. 2011, 21, 3226-3233.
Perez-Temprano, M. H.; Gallego, A. M.; Casares, J. A.;
Carrera, N.; Gutierrez, E.; Benavente, R.; Villavieja, M. M.;
9
ACKNOWLEDGMENT
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This project has received funding from the European Research
Council (ERC) under the European Union’s Horizon 2020
research and innovation programme (Grant no. 638337).
This work is supported by the Cluster of Excellence RESOLV
(EXC 1069) funded by the Deutsche Forschungsgemeinschaft.
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2001, 7, 2481-2489.
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Wunderlich, S. H.; Knochel, P., Angew. Chem. Int. Ed.
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