Selective Suzuki-Miyaura monocouplings with symmetrical dibromoarenes and aryl ditriflates for the one-pot synthesis of unsymmetrical triaryls

Article abstract of DOI:10.1002/ejoc.201400090

The various parameters that would permit selective Suzuki-Miyaura monocouplings of symmetrical dihaloarenes were studied. High selectivity and efficiency can be obtained for a broad range of substrates by using operationally simple conditions and widely available reagents. The 38 different examples described provide a valuable toolbox for the rapid access to unsymmetrical triaryls, as illustrated by the preparation of diarylpyridine 8, terphenyl 9, and diarylpyrrole 10. By studying several key parameters, the factors that allow selective Suzuki-Miyaura monocoupling of symmetrical dihaloarenes have been outlined. This study serves as the basis for the efficient synthesis of unsymmetrical triaryls from symmetrical dibromoarenes and aryl ditriflates by a one-pot desymmetrizing double Suzuki-Miyaura coupling. Copyright

Full text of DOI:10.1002/ejoc.201400090

Job/Unit: O40090
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Date: 26-03-14 17:30:37
Pages: 15
FULL PAPER
DOI: 10.1002/ejoc.201400090
Selective Suzuki–Miyaura Monocouplings with Symmetrical Dibromoarenes
and Aryl Ditriflates for the One-Pot Synthesis of Unsymmetrical Triaryls
Corinne Minard,[a] Carole Palacio,[a] Kevin Cariou,[a] and Robert H. Dodd*[a]
Keywords: Synthetic methods / C–C coupling / Cross-coupling / Palladium
The various parameters that would permit selective Suzuki–
Miyaura monocouplings of symmetrical dihaloarenes were
studied. High selectivity and efficiency can be obtained for
a broad range of substrates by using operationally simple
conditions and widely available reagents. The 38 different
examples described provide a valuable toolbox for the rapid
access to unsymmetrical triaryls, as illustrated by the prepa-
ration of diarylpyridine 8, terphenyl 9, and diarylpyrrole 10.
from dibromoarenes (though this is mainly limited to ortho-
disubstituted compounds, for which steric interactions al-
ready tend to favor the formation of a monoarylated ad-
duct).[7] McNulty conducted a similar study on dichloro-
benzenes,[8] and the Langer group developed various sets
of conditions for the selective coupling of polyhalogenated
substrates.[9] We have previously shown that, as electron-
rich arylboronic acids react faster than their electron-poor
counterparts, selective monoarylations (with indole boronic
acid)[10] and one-pot simultaneous dicouplings to yield un-
symmetrical adducts could be performed.[11] This latter ap-
proach can be extremely valuable for accessing biologically
interesting targets such as lamellarin A4 and G,[12] ningalin
B,[13] and their analogs (Figure 1).[14]
Introduction
Polyaromatic sequences are widely found in a large vari-
ety of organic compounds of both biological and physical
interest. As a consequence, many procedures have been de-
veloped for their preparation. Metal-catalyzed cross-cou-
pling reactions[1] and, most prominently, the Suzuki–Mi-
yaura reaction[2] probably constitute the most efficient stra-
tegies to construct these scaffolds through C–C bond for-
mation. However, the construction of an unsymmetrical tri-
aryl requires a certain degree of discrimination between the
various reactive sites. The use of two different halides or
pseudohalides allows such a differentiation but often re-
quires tedious stepwise protocols for the preparation of the
starting material.[3] An alternative lies in the synthesis of a
substrate bearing identical halides with different steric and/
or electronic environments.[4] A simpler approach would be
to use more readily available symmetrical dihaloarenes and
to perform a selective monocoupling to ensure the desym-
metrization of the starting material. The resulting halodiar-
ene would then constitute a versatile platform for subse-
quent functionalization. Despite its apparent simplicity,
only a handful of studies have been fully devoted to this
strategy. In 2005, Uozumi reported that such a monoaryl-
ation of dibromoarenes could be achieved by using an am-
phiphilic supported palladium(II) complex and an excess of
triphenylphosphine,[5] but Sherburn showed that diarylation
was the preferred outcome for diiodoarenes, whereas
monoarylation of dibromoarenes could be achieved by
using them in excess.[6] More recently, Hu also described
that the use of an excess of triphenylphosphine could ef-
ficiently favor the formation of monoarylated compounds
Figure 1. Natural marine triaryl compounds.
However, our one-pot procedure is somewhat limited by
the necessity that each reactant has different electron den-
sity, and studies by other groups also have some limitations
in terms of scope and practicality.[5,7] Indeed, a widely ap-
plicable and general strategy for this purpose is still needed
by the synthetic community. In this context, we sought to
study the monocoupling of various symmetrical aryl di-
bromides and ditriflates with a representative panel of
boron derivatives to develop an efficient and operationally
simple protocol that could eventually be amenable to one-
pot desymmetrizing difunctionalization procedures. An ex-
[a] Centre de Recherche de Gif, Institut de Chimie des Substances
Naturelles, UPR 2301, CNRS,
Avenue de la Terrasse, 91198 Gif-sur-Yvette, France
E-mail: robert.dodd@cnrs.fr
http://www.icsn.cnrs-gif.fr/spip.php?article36
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201400090.
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C. Minard, C. Palacio, K. Cariou, R. H. Dodd
FULL PAPER
amination of the mechanism of the Suzuki–Miyaura cross- would render this step rate-determining would increase the
coupling reveals that a certain control over the oxidative
addition is required to favor the monocoupling. Indeed,
oxidative addition of the 14-electron Pd0 complex to one of
the two C–X bonds of dihalo compound 1 would give rise
to complex 2 (Scheme 1). After a ligand exchange between
X and a hydroxide ion, transmetallation with the boronic
acid[15] followed by reductive elimination would then deliver
the desired halodiaryl 3. At this stage, the 14-electron Pd0
species is regenerated and can either react with 1, which is
the desired manifold, or react with 3 to generate complex 4
and, thereafter, the unwanted symmetrical triaryl 5.
chance of a selective monocoupling pathway. In addition to
the properties of the dihaloarene, three parameters ap-
peared as potentially critical and relatively flexible: the tem-
perature, the nature of the boron species,[16] and the Pd/
ligand ratio.[7] We started our study by reacting 1 equiv. of
2,6-dibromopyridine (1a) with 1 equiv. of p-ethoxyphenyl-
boronic acid as benchmark compounds in toluene/EtOH/
H2O (4:1:2) in the presence of 8 equiv. of base (Na2CO3),
50 mol-% of KCl, and 0.5 mol-% of Pd(PPh3)4 (Table 1, En-
try 1).[17] Tetrakis(triphenylphosphine)palladium(0) was
chosen because this catalyst is widely available, quite robust,
and also slowly generates the 14-electron species. Under
these conditions, the monoarylated adduct 3aa was the
major product, but a significant amount of unwanted di-
arylpyridine 5aa was also observed. Under the same condi-
tions, the corresponding potassium trifluoroborate gave
better results in terms of selectivity (Table 1, Entry 2). We
then decided to use a slightly higher amount of catalyst but
in conjunction with a twofold excess of triphenylphosphine.
Thus, at a Pd/L ratio of 1:6, the amount of active 14-elec-
tron Pd0 complex available would be lower and the oxidat-
ive addition to the more reactive dibromopyridine 1a would
be favored.[18] In this case, the boronic acid and the tri-
fluoroborate exhibited identical reactivity and selectivity,
but the 87:13 ratio observed was not entirely satisfactory
(Table 1, Entries 3 and 4). We then lowered the temperature
to r.t., which proved detrimental to the reactivity, as full
conversion was only obtained after two days, but the selec-
tivity was increased to 95:5 (Table 1, Entries 5 and 6). When
boronic esters [both pinacol (pin) and neopentyl glycol
(neopent)] were used, the selectivity was complete, but the
Scheme 1. Mono- vs. dicoupling.
Results and Discussion
In theory, the initial dihalo compound 1 should be
slightly more reactive than the resulting monohaloarene 3
toward the oxidative addition and, thus, any factor that
Table 1. Monocoupling optimization.
Entry “B”
Pd [mol-%] PPh3 [mol-%] Temp. [°C] Na2CO3 [equiv.]
t
Conv.[a] [%]
3/5[a]
Yield[b] [%]
1
2
3
4
5
6
7
8
B(OH)2
BF3K
B(OH)2
BF3K
B(OH)2
BF3K
0.5
0.5
3
3
3
3
3
3
3
3
3
3
3
3
3
3
0
0
6
6
6
6
6
6
6
6
6
6
6
6
6
6
100
100
100
100
r.t.
r.t.
r.t.
r.t.
40
40
40
40
40
8
8
8
8
8
8
8
8
8
8
8
8
4
4
4
4
1.5 h
1.5 h
2.5 h
2.5 h
2 d
2 d
2 d
2 d
6 h
6 h
6 h
6 h
6 h
100
100
100
100
100
100
13
67:33
90:10
87:13
87:13
95:5
–
–
–
–
–
–
–
–
–
–
–
–
70
85
42
51
95:5
B(pin)
100:0
100:0
91:9
95:5
95:5
91:9
91:9
95:5
95:5
B(neopent)
B(OH)2
BF3K
21
9
100
100
Ͻ50
Ͻ50
100
100
Ͻ50
Ͻ50
10
11
12
13
14
15
16
B(pin)
B(neopent)
B(OH)2
BF3K
B(pin)
B(neopent)
40
40
40
6 h
6 h
6 h
95:5
1
[a] Determined by H NMR analysis of the crude product mixtures. [b] Isolated yields.
2
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Selective Suzuki–Miyaura Monocouplings
conversion was extremely low even after 2 d (Table 1, En- time allowed isolation of 62% of the desired compound
tries 7 and 8). To find a balance between reactivity and (Table 2, Entry 5). ortho-Substituted boron reagents were
selectivity, the temperature was increased to 40 °C. Total expected to be problematic as steric effects would now be
reaction was now observed after 6 h, except for the boronic at play. Indeed, only modest yields of monocoupled product
esters, and the selectivity remained excellent (Table 1, En- were obtained with o-F, o-OMe, and o-OBn phenyltri-
tries 9–12) for all compounds. Finally, with only 4 equiv. of fluoroborates at 40 °C (34–53%; Table 2, Entries 6–8).
base (Table 1, Entries 13–16), both conversion and selectiv-
Nevertheless, an increased temperature of 70 °C allowed
ity remained virtually unchanged, but the best yield of iso- the steric hindrance to be overcome and led to satisfactory
lated monocoupled product was obtained with the tri- yields (54–70%). In this case, the loss of selectivity that
fluoroborate (85%; Table 1, Entry 14).
could be expected at a higher reaction temperature was tem-
Here, the nature of the boron function plays an impor- pered by the addition of more triphenylphosphine and
tant role as, in our hands, potassium trifluoroborates were shorter reaction times. Finally, (3,4-dimethoxyphenyl)tri-
more conducive to higher yields. Although their advantages fluoroborate was tested (Table 2, Entry 9). Although the
are now well established,[19] their robustness is crucial for yield was moderate at 40 °C (47%), an increased tempera-
selective monocouplings, as an excess of boron derivative ture of 70 °C only proved detrimental; the main issue is that
(which could be counterproductive) is not necessary to at- the high reactivity of this compound tends to favor dicou-
tain high yields.
pling.
The next step was to test these conditions with a wider
Having determined the optimal conditions for this
monocoupling, we next varied the substituents of the tri- range of symmetrical dibromoarenes and -heteroarenes as
fluoroborate partner. We first used para-substituted com- the electronic properties of the trifluoroborate partner were
pounds so that only electronic rather than steric effects varied. First, 3,5-dibromopyridine (1b) was treated with 4-
would be at play (Table 2, Entries 1–4). Substituents with OEt-, 4-CH3- and 4-NO2-C6H4BF3K, and the results were
limited electronic effects such as methyl and fluoride re- quite similar to those obtained with 2,6-dibromopyridine
acted smoothly to afford the desired bromodiaryls in 69 and and gave moderate-to-good yields of the desired bromodi-
70% yield. On the other hand, electron-withdrawing groups arenes (64–76%; Table 3, Entries 1–3). With m- (1c; Table 3,
such as nitro and trifluoromethyl gave lower yields, which Entries 4–6) and p-dibromobenzene (1d; Table 3, Entries 7–
could not be improved by increasing the temperature to 9), the same trend was observed: borates substituted with
compensate for their lower reactivity. In the latter case, it is
also important to note that the difference of reactivity for
the oxidative addition step between the starting dibromoar-
Table 3. Monocoupling of various symmetrical dibromoarenes.
ene and the monocoupled product is lowered because of the
electron-withdrawing nature of the newly introduced moi-
ety; thus, the selective process is potentially disfavored. (m-
Methoxyphenyl)trifluoroborate reacted poorly at 40 °C, but
an increased temperature of 70 °C and a shorter reaction
Table 2. Monocoupling of 2,6-dibromopyridine.
Entry Dibromoarene
R
3
Temp. Yield[a]
[°C]
[%]
1
2
3
4
5
6
7
8
3,5-dibromopyridine (1b)
OEt 3ba
CH3 3bb
NO2 3bc
OEt 3ca
CH3 3cb
NO2 3cc
OEt 3da
CH3 3db
NO2 3dc
OEt 3ea
CH3 3eb
NO2 3ec
40
40
40
40
40
40
40
40
40
70
70
70
76
76
64
82
77
47
76
73
55
1b
1b
1,3-dibromobenzene (1c)
1c
1c
1,4-dibromobenzene (1d)
Entry
R
3
Temp.
[°C]
Yield
[%]
Temp.
[°C]
Yield[a]
[%]
1d
1d
9
1
2
3
4
5
6
7
8
9
4-CH3
4-F
4-NO2
4-CF3
3-OMe
2-F
2-OMe
2-OBn
3,4-OMe
3ab
3ad
3ac
3ae
3af
3ag
3ah
3ai
40
40
40
40
40
40
40
40
40
69
70
63
45
38
44
34
53
47
–
–
–
–
55
10
11
12
13
14
15
16
17
18
1,2-dibromobenzene (1e)
49
1e
1e
1e
1e
1e
49[b]
33
100
70
70
70
70
70
70
22[b]
62[c]
54[b]
70[c]
65[b]
34[d]
OEt 3ea 100
CH3 3eb 100
NO2 3ec
74
40
100
70
70
49
2,5-dibromothiophene (1f) OEt 3fa
1f
1f
53[c]
45[c]
45
CH3 3fb
3fd
3aj
F
70
[a] Isolated yields. [b] 4 h reaction time, 12 mol-% PPh3. [c] 4 h reac-
[a] Isolated yields. [b] Conversion as determined by analysis of the
1H NMR spectrum: 49% of 3, 39% of 1, and 12% of the dicoupled
product. [c] 1.5 equiv. of ArBF3K.
tion time. [d] 4 h reaction time, a 7:3 ratio for 3aj/5aj was deter-
1
mined by analysis of the crude product by H NMR spectroscopy.
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electron-donating groups (EDGs) gave yields above 70% from hydroquinone, and different para-ethoxybenzene-
(Table 3, Entries 4–5 and 7–8), whereas borates substituted boron derivatives (Table 4, Entries 1–4) clearly showed that
with electron-withdrawing groups (EWGs) led to the de- the potassium trifluoroborate salt was again the optimal
sired compound with yields of ca. 50% (Table 3, Entries 6 choice for a high-yielding mono-cross-coupling reaction
and 9). In these latter cases, a significant amount of dicou- (93%; Table 4, Entry 2). However, although the p-tolyltri-
pling product was also observed. Owing to the limited elec- fluoroborate gave a satisfactory yield of 69% (Table 4, En-
tronic differentiation between the dibromo starting material try 5), the p-nitro derivative only led to a complex mixture
and the monoarylated adduct, the product distribution (Table 4, Entry 6). Resorcinol ditriflate (6b) exhibited a
tends to be roughly statistical (i.e., a 1:2:1 distribution for lower reactivity, which could readily be enhanced at a
1/3/5).
higher temperature of 70 °C and a longer reaction time of
For o-dibromobenzene (1e), the steric interactions, which 20 h to provide the p-OEt and p-Me products with good
could favor a selective monocoupling,[7] mostly proved det- yields (Table 4, Entries 7 and 8). Even the p-NO2 product
rimental as the reaction mixture had to be heated to 70 °C was obtained with a satisfactory 57% yield under these con-
to reach moderate yields (Table 3, Entries 10–12). An in- ditions (Table 4, Entry 9). In the case of catechol ditriflate
creased reaction temperature of 100 °C was necessary to (6c), the same trend was observed even at 70 °C, but the
produce yields comparable to those obtained with 1c and yields were lower, probably because of the unfavorable steric
1d, except in the case of the tolylboronate, for which purifi- interactions (Table 4, Entries 10–12). Finally, pyrrole 6d,
cation of the desired compound proved challenging which constitutes a key starting material for lamellarin- and
(Table 3, Entries 13–15). Finally, 2,5-dibromothiophene (1f) ningalin-like derivatives,[14] was submitted to the same reac-
was also tested in this reaction and, despite extensive opti- tion conditions. At 70 °C, excellent yields could be observed
mization trials, only low-to-moderate yields could be at- by NMR spectroscopy for both the p-OEt and the p-Me
tained even when an excess of the boron reagent was used compound, but both products proved quite sensitive to
(Table 3, Entries 16–18).
chromatographic purification (Table 4, Entries 13 and 14).
To further broaden the scope of this study, we then For (p-nitrophenyl)trifluoroborate, the desired mono-
turned our attention to various arene ditriflates, which can coupled adduct could only be isolated in a modest 31%
generally be easily accessed from readily available diphenols yield (Table 4, Entry 15). Owing to the electron-with-
and, therefore, constitute valuable synthons. We first wished drawing nature of the group introduced, the monocoupled
to verify which boron function was the most suitable in this product was quite reactive as evidenced by the isolation of
case. The reaction (with the same operating conditions as 34% of the dicoupled adduct, and 27% of the unreacted
for the dibromoarenes) between the ditriflate 6a, derived starting material was also recovered.
Table 4. Monocoupling optimization on ditriflates.
En-
try
Arene ditriflate
B
R
7
Temp. [°C]
t [h]
Yield [%][a]
1
2
3
4
5
6
7
8
benzene-1,4-ditriflate (6a)
B(OH)2
BF3K
B(pin)
B(neopent)
BF3K
BF3K
BF3K
BF3K
BF3K
BF3K
BF3K
BF3K
BF3K
BF3K
BF3K
OEt
OEt
OEt
OEt
CH3
NO2
OEt
CH3
NO2
OEt
CH3
NO2
OEt
CH3
NO2
7aa
7aa
7aa
7aa
7ab
7ac
7ba
7bb
7bc
7ca
7cb
7cc
7da
7db
7dc
40
40
40
40
40
40
70
70
70
70
70
70
70
70
70
6
6
6
6
6
86
93
67
6a
6a
6a
64
6a
69
6a
6
c.m.[b]
78
benzene-1,3-ditriflate (6b)
20
20
20
20
20
20
20
20
20
6b
6b
70
57
65
62
9
10
11
12
13
14
15
benzene-1,2-ditriflate (6c)
6c
6c
6d
6d
6d
38
51 (75)[c]
57 (75)[c]
31[d]
1
[a] Isolated yields. [b] c.m.: complex mixture. [c] Conversion as determined by H NMR spectroscopy: 75% of 7, 18% of 6, and 7% of
the dicoupled product. [d] 34% of the symmetrical dicoupled product and 27% of the starting material were isolated.
4
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Selective Suzuki–Miyaura Monocouplings
Scheme 2. One-pot synthesis of unsymmetrical triaryls.
The usefulness of the monocoupling strategy and the ro- yloxyphenyl)boronic acid to give diarylpyrrole 10 in a 76%
bustness of our conditions were ascertained by the ac- isolated yield (Scheme 2, Equation 4).
complishment of one-pot desymmetrizing double Suzuki–
This latter example is remarkable because it paves the
Miyaura couplings to give the desired triaryl derivatives.[20] way for the rapid construction of libraries of ningalin B
The optimized monocoupling conditions (with double the analogs from a common platform and isolation of the un-
amount of base introduced) were first applied to dibromo- stable intermediate monotriflate is avoided; thus, the target
pyridine 1a with potassium (p-ethoxyphenyl)trifluoroborate compound can be obtained in an excellent yield.
to give arylpyridine 3aa, which was not isolated. After the
requisite 6 h, potassium (p-fluorophenyl)trifluoroborate
was added, and the reaction mixture was heated at 100 °C
for 2 h. This method allowed the isolation of the unsymmet-
Conclusions
rical diarylpyridine 8 in an excellent 83% yield (Scheme 2,
We have shown that selective Suzuki–Miyaura mono-
Equation 1). A similar procedure was then applied to 1,3- cross-coupling can be accomplished with a wide range of
dibromobenzene 1c (Scheme 2, Equation 2) and resorcinol symmetrical dihaloarenes under operationally simple condi-
ditriflate 6b (Scheme 2, Equation 3) by using potassium (p- tions. By adjusting several parameters such as the catalyst/
ethoxyphenyl)trifluoroborate (under the optimized condi- ligand ratio and the temperature, the desired adducts can
tions described in Table 3, Entry 4 for 1c and Table 4, En- be obtained in good yields without elaborate ligands and/
try 7 for 6b) followed by (p-trifluoromethylphenyl)boronic or catalyst systems or the use of an excess of the dihalo
acid. The corresponding terphenyl 9 was obtained in both compound. A key feature that emerged from this study is
cases in a satisfactory yield (58 and 62%, respectively), con- that the most suitable substrates for selective coupling are
sidering the lower reactivity of p-trifluoromethyl-substi- the EDG-bearing arylboron derivatives. Indeed, the EDG
tuted boron reagents.[21] Finally, this protocol was also im- has the doubly beneficial role of enhancing the first cou-
plemented for pyrrole ditriflate 6d by using potassium (3,4- pling, which can in turn be performed at a lower tempera-
dimethoxyphenyl)trifluoroborate (under the optimized con- ture, and of increasing the difference in reactivity between
ditions described in Table 4, Entry 13) followed by (o-benz- the dihaloarene and the resulting halodiaryl. This has an
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C. Minard, C. Palacio, K. Cariou, R. H. Dodd
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septum and placed under an argon atmosphere. Tetrakis(triphenyl-
phosphine)palladium(0) (3 mol-%) was then added, and a mixture
of freshly degassed toluene/ethanol/water (4:1:2 v/v/v) was injected
with a syringe. The septum was replaced by a screw cap, the tube
was sealed, and the reaction mixture was stirred at the appropriate
temperature (40–100 °C) for 6–20 h. The resulting mixture was then
cooled to room temp., extracted with ethyl acetate, and washed
with water. The combined organic layers were dried with MgSO4
and concentrated under reduced pressure. Purification of the re-
sulting crude material was performed by flash silica gel chromatog-
impact on the order of the couplings if one wishes to intro-
duce an EDG and an EWG on the same framework. Thus,
the moiety bearing the electron-withdrawing substituent
should be incorporated in a second coupling, as the lower
reactivity of these compounds can then be compensated by
using harsher conditions. Finally, although these selective
monocouplings can grant access to many valuable synthons
for further transformations, they also offer opportunities
for a second Suzuki–Miyaura cross-coupling to rapidly ac-
cess triaryl scaffolds. This was showcased by highly efficient raphy or preparative TLC with an appropriate solvent system.
desymmetrizing one-pot double Suzuki–Miyaura reactions
of 2,6-dibromopyridine (1a), 1,3-dibromobenzene (1c), res-
orcinol ditriflate (6b), and 2,5-bis(ethoxycarbonyl)pyrrol-
3,4-diol ditriflate (6d). Further efforts in this direction, in-
General Procedure B – Suzuki–Miyaura One-Pot Double Couplings:
The aryl dibromide (or aryl ditriflate, 1 equiv.), the first boron de-
rivative (1 equiv.), sodium carbonate (8 equiv.), potassium chloride
(0.5 equiv.), and triphenylphosphine (6 mol-%) were successively in-
troduced to a sealable tube. The tube was capped with a rubber
cluding the preparation and evaluation of libraries of biolo-
gically relevant compounds, are underway in our laboratory septum and placed under an argon atmosphere. Tetrakis(triphenyl-
phosphine)palladium(0) (3 mol-%) was then added, and a mixture
of freshly degassed toluene/ethanol/water (4:1:2, v/v/v) was injected
with a syringe. The septum was replaced by a screw cap, the tube
was sealed, and the reaction mixture was stirred at the appropriate
temperature (40–100 °C) for 6–20 h. The mixture was then cooled
until reflux stopped, and the second boron derivative (1 equiv.) was
then added. Again, the tube was sealed, and the reaction mixture
was stirred at the appropriate temperature (40–100 °C) for an ad-
ditional 6–20 h. The resulting mixture was then cooled to room
temp., extracted with ethyl acetate, and washed with water. The
combined organic layers were dried with MgSO4 and concentrated
under reduced pressure. Purification of the resulting crude material
was performed by flash silica gel chromatography or preparative
TLC with an appropriate solvent system.
and will be reported in due course.
Experimental Section
General Methods: Melting points were measured in capillary tubes
with a Büchi B-540 apparatus. Infrared spectra were recorded with
a Perkin–Elmer Spectrum BX FTIR spectrometer. 1H and 13C
NMR spectra were recorded with Bruker spectrometers: Avance
300 MHz (a QNP probe for 13C, 31P, 19F or a dual 13C probe) and
Avance 500 MHz (BB0 ATM or BBI ATM probe). 13C NMR spec-
tra were recorded at 125 or 75 MHz by using a broadband-decou-
pled mode, and the multiplicities were obtained by using a JMOD
or DEPT sequence. NMR experiments were performed in deuter-
iochloroform (CDCl3), and chemical shifts (δ) are reported in parts
per million (ppm) with reference to CDCl3 (1H: δ = 7.24 ppm; 13C:
δ = 77.23 ppm). The following abbreviations are used for the proton
spectra multiplicities: s singlet, d doublet, t triplet, q quartet, hept
heptuplet, m multiplet, br broad. Coupling constants (J) are re-
ported in hertz [Hz]. Mass spectra were obtained either with an
LCT (Micromass) instrument by electrospray ionization (ES) or
from a time-of-flight analyzer (ESI-MS) for the high-resolution
mass spectra (HRMS). Atmospheric pressure photoionization
(APPI) spectra were obtained with an Agilent 1290 Infinity SFC
instrument with a Q-ToF 6540 analyzer. Analytical thin-layer
chromatography was performed with silica gel 60 F254 on alumi-
num plates (Merck), which were visualized under a UVP Min-
eralight UVLS-28 lamp (254 nm) and with ninhydrin and p-anisal-
dehyde stains. Preparative thin-layer chromatography was per-
formed with silica gel 60 F254 (Merck, 0.5 mm). Flash chromatog-
raphy was conducted with Merck silica gel 60 (40–63 μm) at me-
dium pressure (300 mbar) or with a CombiFlash apparatus (Ser-
labo Technologies) with standard settings. For Suzuki–Miyaura
couplings, solvents were always freshly degassed with argon. Or-
ganic extracts were dried with magnesium sulfate (MgSO4). All rea-
gents were obtained from commercial suppliers unless otherwise
stated. All boronic acids were obtained from Frontier Scientific,
and other boronic compounds (potassium organotrifluorobor-
ates[19] and boronic esters)[22] were prepared by following literature
procedures. Pyrrole derivatives were also synthesized according to
literature procedures.[14a]
2-Bromo-6-(4-ethoxyphenyl)pyridine (3aa): Compound 3aa was pre-
pared according to general procedure A by reacting 2,6-di-
bromopyridine (46 mg, 0.2 mmol) with potassium (4-ethoxyphen-
yl)trifluoroborate (46 mg, 0.2 mmol), sodium carbonate (85 mg,
0.8 mmol), potassium chloride (7 mg, 0.1 mmol), triphenylphos-
phine (3.0 mg, 6 mol-%), and tetrakis(triphenylphosphine)palla-
dium(0) (7.0 mg, 3 mol-%) in a mixture of degassed toluene/ethanol
(1.40:0.35 mL) and degassed water (0.70 mL). The reaction mixture
was stirred at 40 °C for 6 h. After extraction, purification of the
crude material by flash chromatography on silica gel (0 to 20%
EtOAc in heptane) afforded 3aa as a white powder (46 mg, 85%).
1H NMR (300 MHz, CDCl3): δ = 1.42 (t, J = 6.9 Hz, 3 H), 4.06
(q, J = 6.9 Hz, 2 H), 6.94 (d, J = 8.8 Hz, 2 H), 7.31 (dd, J = 7.6,
1.0 Hz, 1 H), 7.51 (dd, J = 7.8, 7.6 Hz, 1 H), 7.58 (dd, J = 7.8,
1.0 Hz, 1 H), 7.91 (d, J = 8.8 Hz, 2 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 15.0 (CH3), 63.8 (CH2), 114.8 (2 CH), 118.3 (CH),
125.6 (CH), 128.5 (2 CH), 130.2 (C), 139.1 (CH), 142.2 (C), 158.5
(C), 160.5 (C) ppm. IR (neat): ν = 2975, 2926, 1606, 1574, 1547,
˜
1512, 1432, 1421, 1392, 1251, 1115, 1042, 790 cm–1. HRMS (ESI):
calcd. for C13H1379BrNO [M + H]+ 278.0102; found 278.0173;
calcd. for C13H1381BrNO [M + H]+ 280.0082; found 280.0151.
2-Bromo-6-(p-tolyl)pyridine (3ab): Compound 3ab was prepared ac-
cording to general procedure A by reacting 2,6-dibromopyridine
(46 mg, 0.2 mmol) with potassium (4-methylphenyl)trifluoroborate
(40 mg, 0.2 mmol), sodium carbonate (85 mg, 0.8 mmol), potas-
sium chloride (7 mg, 0.1 mmol), triphenylphosphine (3.0 mg,
6 mol-%), and tetrakis(triphenylphosphine)palladium(0) (7.0 mg,
3 mol-%) in a mixture of degassed toluene/ethanol (1.40:0.35 mL)
and degassed water (0.70 mL). The reaction mixture was stirred at
40 °C for 6 h. After extraction, purification of the crude material
by flash chromatography on silica gel (0 to 40% CH2Cl2 in hept-
General Procedure A – Suzuki–Miyaura Monocouplings: The aryl
dibromide (or aryl ditriflate, 1.0 equiv.), the boron derivative
(1.0 equiv.), sodium carbonate (4.0 equiv.), potassium chloride
(0.5 equiv.), and triphenylphosphine (6 mol-%) were successively in-
troduced to a sealable tube. The tube was capped with a rubber
6
www.eurjoc.org
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O40090
/KAP1
Date: 26-03-14 17:30:37
Pages: 15
Selective Suzuki–Miyaura Monocouplings
ane) afforded 3ab as a white powder (34 mg, 69%). 1H NMR
(300 MHz, CDCl3): δ = 2.39 (s, 3 H), 7.25 (d, J = 8.2 Hz, 2 H),
7.35 (dd, J = 7.6, 0.9 Hz, 1 H), 7.54 (dd, J = 7.7, 7.6 Hz, 1 H), 7.63
(300 MHz, CDCl3): δ = 7.46 (dd, J = 7.7, 1.0 Hz, 1 H), 7.62 (t, J
= 7.7 Hz, 1 H), 7.67–7.73 (m, 3 H), 8.09 (d, J = 8.0 Hz, 2 H) ppm.
13C NMR (75 MHz, CDCl3): δ = 119.6 (CH), 124.5 (q, J =
(dd, J = 7.7, 0.9 Hz, 1 H), 7.87 (d, J = 8.2 Hz, 2 H) ppm. 13C 270.5 Hz, CF3), 126.0 (q, J = 3.8 Hz, 2 CH), 127.5 (2 CH), 127.6
NMR (75 MHz, CDCl3): δ = 21.5 (CH3), 118.1 (CH), 126.1 (CH), (CH), 132.2 (q, J = 47.5 Hz, C), 138.3 (C), 139.4 (CH), 141.1 (C),
127.1 (2 CH), 129.7 (2 CH), 135.1 (C), 139.1 (CH), 140.0 (C), 142.3
142.7 (C) ppm. IR (neat): ν = 3079, 2927, 1575, 1551, 1432, 1312,
˜
(C), 158.8 (C) ppm. IR (neat): ν = 3028, 2913, 2855, 1579, 1544,
1110, 1072, 848, 793, 747 cm–1. HRMS (ESI): calcd. for
C12H879BrF3N [M + H]+ 301.9714; found 301.9814; calcd. for
C12H881BrF3N [M + H]+ 303.9693; found 303.9799.
˜
1512, 1429, 1413, 1124, 790 cm–1. HRMS (ESI): calcd. for
C12H1179BrN [M + H]+ 247.9997; found 248.0081; calcd. for
C12H1181BrN [M + H]+ 249.9976; found 250.0058.
2-Bromo-6-(3-methoxyphenyl)pyridine (3af): Compound 3af was
prepared according to general procedure A by reacting 2,6-di-
bromopyridine (46 mg, 0.2 mmol) with potassium (3-methoxy-
phenyl)trifluoroborate (43 mg, 0.2 mmol), sodium carbonate
(85 mg, 0.8 mmol), potassium chloride (7 mg, 0.1 mmol), tri-
phenylphosphine (3.0 mg, 6 mol-%), and tetrakis(triphenylphos-
2-Bromo-6-(4-nitrophenyl)pyridine (3ac): Compound 3ac was pre-
pared according to general procedure A by reacting 2,6-dibromo-
pyridine (46 mg, 0.2 mmol) with potassium (4-nitrophenyl)trifluo-
roborate (46 mg, 0.2 mmol), sodium carbonate (85 mg, 0.8 mmol),
potassium chloride (7 mg, 0.1 mmol), triphenylphosphine (3.0 mg,
6 mol-%), and tetrakis(triphenylphosphine)palladium(0) (7.0 mg, phine)palladium(0) (7.0 mg, 3 mol-%) in a mixture of degassed tol-
3 mol-%) in a mixture of degassed toluene/ethanol (1.40:0.35 mL)
and degassed water (0.70 mL). The reaction mixture was stirred at
40 °C for 6 h. After extraction, purification of the crude material by
flash chromatography on silica gel (0% to 20% EtOAc in heptane)
uene/ethanol (1.40:0.35 mL) and degassed water (0.70 mL). The re-
action mixture was stirred at 70 °C for 4 h. After extraction, purifi-
cation of the crude material by preparative TLC (30% CH2Cl2 in
1
heptane) afforded 3af as a white powder (32 mg, 62%). H NMR
afforded 3ac as
a
yellow powder (35 mg, 63%). 1H NMR
(300 MHz, CDCl3): δ = 3.87 (s, 3 H), 6.93–6.99 (m, 1 H), 7.34 (d,
J = 7.7 Hz, 1 H), 7.39 (d, J = 7.7 Hz, 1 H), 7.45–7.58 (m, 2 H),
7.58 (d, J = 7.7 Hz, 1 H), 7.65 (d, J = 7.7 Hz, 1 H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 55.6 (CH3), 112.5 (CH), 115.8 (CH), 119.4
(300 MHz, CDCl3): δ = 7.50 (dd, J = 7.9, 0.9 Hz, 1 H), 7.66 (dd,
J = 7.7, 7.9 Hz, 1 H), 7.75 (dd, J = 7.7, 0.9 Hz, 1 H), 8.15 (d, J =
8.8 Hz, 2 H), 8.29 (d, J = 8.8 Hz, 2 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 120.0 (CH), 124.2 (2 CH), 128.0 (2 CH), 128.2 (CH), (CH), 119.6 (CH), 126.7 (CH), 130.0 (CH), 139.2 (CH), 139.3 (C),
139.5 (CH), 142.8 (C), 143.6 (C), 148.7 (C), 156.0 (C) ppm. IR 142.3 (C), 158.6 (C), 160.3 (C) ppm. IR (neat): ν = 3074, 2934,
˜
(neat): ν = 3110, 3085, 2962, 1507, 1343, 1259, 1087, 1047, 1012, 2835, 1575, 1549, 1424, 1217, 1123, 1037, 790 cm–1. HRMS (ESI):
˜
790 cm–1.
HRMS
(ESI):
calcd.
for
C11H879BrN2O2
calcd. for C12H1179BrNO2 [M + H]+ 263.9946; found 264.0012;
calcd. for C12H1181BrNO2 [M + H]+ 265.9925; found 266.0001.
[M + H]+ 278.9691; found 278.9787; calcd. for C11H881BrN2O2 [M
+ H]+ 280.9670; found 280.9781.
2-Bromo-6-(2-fluorophenyl)pyridine (3ag): Compound 3ag was pre-
pared according to general procedure A by reacting 2,6-dibromo-
pyridine (46 mg, 0.2 mmol) with potassium (2-fluorophenyl)trifluo-
roborate (40 mg, 0.2 mmol), sodium carbonate (85 mg, 0.8 mmol),
potassium chloride (7 mg, 0.1 mmol), triphenylphosphine (6.0 mg,
12 mol-%), and tetrakis(triphenylphosphine)palladium(0) (7.0 mg,
3 mol-%) in a mixture of degassed toluene/ethanol (1.40:0.35 mL)
and degassed water (0.70 mL). The reaction mixture was stirred at
70 °C for 4 h. After extraction, purification of the crude material
by preparative TLC (20% CH2Cl2 in heptane) afforded 3ag as a
white powder (27 mg, 54%). 1H NMR (300 MHz, CDCl3): δ = 7.12
(ddd, J = 11.6, 7.9, 1.2 Hz, 1 H), 7.23 (td, J = 7.9, 1.2 Hz, 1 H),
2-Bromo-6-(4-fluorophenyl)pyridine (3ad): Compound 3ad was pre-
pared according to general procedure A by reacting 2,6-dibromo-
pyridine (46 mg, 0.2 mmol) with potassium (4-fluorophenyl)trifluo-
roborate (40 mg, 0.2 mmol), sodium carbonate (85 mg, 0.8 mmol),
potassium chloride (7 mg, 0.1 mmol), triphenylphosphine (3.0 mg,
6.0 mol-%), and tetrakis(triphenylphosphine)palladium(0) (7.0 mg,
3.0 mol-%) in a mixture of degassed toluene/ethanol (1.40:0.35 mL)
and degassed water (0.70 mL). The reaction mixture was stirred at
40 °C for 6 h. After extraction, purification of the crude material
by preparative TLC (20% CH2Cl2 in heptane) afforded 3ad as a
white powder (35 mg, 70%). 1H NMR (300 MHz, CDCl3): δ = 7.12
(t, J = 8.8 Hz, 2 H), 7.38 (dd, J = 7.5, 1.1 Hz, 1 H), 7.56 (t, J = 7.31–7.39 (m, 1 H), 7.41 (d, J = 7.9 Hz, 1 H), 7.57 (t, J = 7.9 Hz,
7.5 Hz, 1 H), 7.61 (dd, J = 7.5, 1.1 Hz, 1 H), 7.96 (dd, J = 8.8, 1 H), 7.76 (dd, J = 7.9, 1.9 Hz, 1 H), 8.01 (td, J = 7.9, 1.9 Hz, 1
5.2 Hz, 2 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 116.0 (d, J = H) ppm. 13C NMR (75 MHz, CDCl3): δ = 116.4 (d, J = 23.0 Hz,
21.8 Hz, 2 CH), 118.8 (CH), 126.5 (CH), 129.1 (d, J = 8.7 Hz, 2 CH), 123.4 (d, J = 10.4 Hz, CH), 124.8 (d, J = 3.1 Hz, CH), 127.0
CH), 134.0 (d, J = 2.9 Hz, C), 139.3 (CH), 142.4 (C), 157.7 (C), (CH), 131.3 (d, J = 12.1 Hz, CH), 131.4 (CH), 138.9 (CH), 142.1
164.1 (d, J = 247.6 Hz, C) ppm. IR (neat): ν = 3079, 2924, 1596,
(C), 154.3 (C), 154.5 (C), 160.7 (d, J = 251.1 Hz, C) ppm. IR (neat):
˜
1578, 1547, 1508, 1428, 1414, 1386, 1227, 1124, 851, 790 cm–1.
HRMS (ESI): calcd. for C11H879BrFN [M + H]+ 251.9746; found
251.9834; calcd. for C11H881BrFN [M + H]+ 253.9725; found
253.9808.
ν = 3075, 2922, 1575, 1547, 1493, 1434, 1393, 1211, 1111, 802,
˜
790 cm–1. HRMS (ESI): calcd. for C11H879BrFN [M + H]+
251.9746; found 251.9818; calcd. for C11H881BrFN [M + H]+
253.9725; found 253.9798.
2-Bromo-6-[4-(trifluoromethyl)phenyl]pyridine (3ae): Compound
3ae was prepared according to general procedure A by reacting 2,6-
dibromopyridine (46 mg, 0.2 mmol) with potassium (4-trifluoro-
methylphenyl)trifluoroborate (50 mg, 0.2 mmol), sodium carbonate
(85 mg, 0.8 mmol), potassium chloride (7 mg, 0.1 mmol), tri-
phenylphosphine (3.0 mg, 6 mol-%), and tetrakis(triphenylphos-
phine)palladium(0) (7.0 mg, 3 mol-%) in a mixture of degassed tol-
uene/ethanol (1.40:0.35 mL) and degassed water (0.70 mL). The re-
action mixture was stirred at 40 °C for 6 h. After extraction, purifi-
cation of the crude material by preparative TLC (10% EtOAc in
2-Bromo-6-(2-methoxyphenyl)pyridine (3ah): Compound 3ah was
prepared according to general procedure A by reacting 2,6-di-
bromopyridine (46 mg, 0.2 mmol) with potassium (2-methoxy-
phenyl)trifluoroborate (43 mg, 0.2 mmol), sodium carbonate
(85 mg, 0.8 mmol), potassium chloride (7 mg, 0.1 mmol), tri-
phenylphosphine (3.0 mg, 6 mol-%), and tetrakis(triphenylphos-
phine)palladium(0) (7.0 mg, 3 mol-%) in a mixture of degassed tol-
uene/ethanol (1.40:0.35 mL) and degassed water (0.70 mL). The re-
action mixture was stirred at 70 °C for 4 h. After extraction, purifi-
cation of the crude material by preparative TLC (30% CH2Cl2 in
1
1
heptane) afforded 3ae as a white powder (27 mg, 45%). H NMR
heptane) afforded 3ah as a white powder (37 mg, 70%). H NMR
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
7

Job/Unit: O40090
/KAP1
Date: 26-03-14 17:30:37
Pages: 15
C. Minard, C. Palacio, K. Cariou, R. H. Dodd
FULL PAPER
(300 MHz, CDCl3): δ = 3.85 (s, 3 H), 6.92 (dd, J = 8.0, 0.7 Hz, 1 EtOAc in heptane) afforded 3ba as a white powder (42 mg, 76%).
H), 7.00 (td, J = 7.9, 1.2 Hz, 1 H), 7.30 (dd, J = 8.0, 0.7 Hz, 1 H),
7.31 (td, J = 7.9, 1.9 Hz, 1 H), 7.47 (t, J = 7.9 Hz, 1 H), 7.78 (dd,
1H NMR (300 MHz, CDCl3): δ = 1.38 (t, J = 7.0 Hz, 3 H), 4.02
(q, J = 7.0 Hz, 2 H), 6.92 (d, J = 8.8 Hz, 2 H), 7.41 (d, J = 8.8 Hz,
J = 7.9, 1.2 Hz, 2 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 55.8 2 H), 7.90–7.96 (m, 1 H), 8.23–9.07 (m, 2 H) ppm. 13C NMR
(CH3), 111.6 (CH), 121.37 (CH), 124.1 (CH), 126.1 (CH), 127.0 (75 MHz, CDCl3): δ = 15.0 (CH3), 63.9 (CH2), 115.4 (3 CH), 128.5
(C), 130.8 (CH), 131.6 (CH), 138.2 (CH), 141.6 (C), 146.9 (C), (3 CH), 128.7 (C), 136.6 (CH), 146.1 (C), 148.7 (C), 159.8 (C) ppm.
157.2 (C) ppm. IR (neat): ν = 2936, 2837, 1573, 1427, 1239, 1124,
IR (neat): ν = 2975, 2926, 1606, 1575, 1547, 1512, 1433, 1421, 1392,
˜
˜
1032, 790 cm–1. HRMS (ESI): calcd. for C12H1179BrNO [M + H] 1251, 1115, 1045, 790 cm–1. HRMS (ESI): calcd. for
263.9946; found 264.0042; calcd. for C12H1181BrNO [M + H]+
265.9925; found 266.0013.
C13H1379BrNO [M + H]+ 278.0102; found 278.0120; calcd. for
C13H1381BrNO [M + H]+ 280.0082; found 280.0113.
+
2-[2-(Benzyloxy)phenyl]-6-bromopyridine (3ai): Compound 3ai was
prepared according to general procedure A by reacting 2,6-di-
bromopyridine (46 mg, 0.2 mmol) with potassium (2-benzyloxy-
phenyl)trifluoroborate (58 mg, 0.2 mmol), sodium carbonate
(85 mg, 0.8 mmol), potassium chloride (7 mg, 0.1 mmol), tri-
phenylphosphine (3.0 mg, 12 mol-%), and tetrakis(triphenylphos-
phine)palladium(0) (7.0 mg, 3 mol-%) in a mixture of degassed tol-
uene/ethanol (1.40:0.35 mL) and degassed water (0.70 mL). The re-
action mixture was stirred at 70 °C for 4 h. After extraction, purifi-
cation of the crude material by preparative TLC (20% CH2Cl2 in
3-Bromo-5-(4-methylphenyl)pyridine (3bb): Compound 3bb was pre-
pared according to general procedure A by reacting 3,5-dibromo-
pyridine (46 mg, 0.2 mmol) with potassium (4-methylphenyl)tri-
fluoroborate (40 mg, 0.2 mmol), sodium carbonate (85 mg,
0.8 mmol), potassium chloride (7 mg, 0.1 mmol), triphenylphos-
phine (3.0 mg, 6 mol-%), and tetrakis(triphenylphosphine)palla-
dium(0) (7.0 mg, 3 mol-%) in a mixture of degassed toluene/ethanol
(1.40:0.35 mL) and degassed water (0.70 mL). The reaction mixture
was stirred at 40 °C for 6 h. After extraction, purification of the
crude material by flash chromatography on silica gel (0 to 20%
EtOAc in heptane) afforded 3bb as a white powder (37 mg, 76%).
1
heptane) afforded 3ai as a white powder (44 mg, 65%). H NMR
(300 MHz, CDCl3): δ = 5.12 (s, 2 H), 7.07 (dd, J = 8.3, 0.7 Hz, 1 1H NMR (300 MHz, CDCl3): δ = 2.39 (s, 3 H), 7.27 (d, J = 8.1 Hz,
H), 7.12 (td, J = 7.7, 1.1 Hz, 1 H), 7.25–7.40 (m, 7 H), 7.52 (t, J =
7.7 Hz, 1 H), 7.89 (dd, J = 7.7, 1.7 Hz, 1 H), 7.90 (dd, J = 7.7,
2 H), 7.43 (d, J = 8.1 Hz, 2 H), 7.97–7.98 (m, 1 H), 8.61 (s, 1 H),
8.72 (s, 1 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 21.4 (CH3),
0.7 Hz, 1 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 70.9 (CH2), 121.1 (C), 127.2 (2 CH), 130.1 (2 CH), 133.6 (C), 136.8 (CH), 138.4
113.3 (CH), 121.7 (CH), 124.2 (CH), 126.1 (CH), 126.7 (C), 127.3
(2 CH), 128.1 (CH), 128.7 (2 CH), 130.7 (CH), 131.7 (CH), 137.0
(C), 139.0 (C), 146.4 (CH), 149.2 (CH) ppm. IR (neat): ν = 3024,
˜
2917, 2854, 1739, 1433, 1377, 1218, 1107, 1008, 825 cm–1. HRMS
(C), 138.2 (CH), 141.6 (C), 156.4 (C), 157.2 (C) ppm. IR (neat): ν (ESI): calcd. for C12H1179BrN [M + H]+ 247.9997; found 248.0088;
˜
= 2923, 2854, 1600, 1573, 1428, 1391, 1127, 1007, 790 cm–1. HRMS calcd. for C12H1181BrN [M + H]+ 249.9976; found 250.0066.
(ESI): calcd. for C18H1579BrNO [M + H]+ 340.0259; found
3-Bromo-5-(4-nitrophenyl)pyridine (3bc): Compound 3bc was pre-
pared according to general procedure A by reacting 3,5-dibromo-
pyridine (46 mg, 0.2 mmol) with potassium (4-nitrophenyl)trifluo-
340.0314; calcd. for C18H1581BrNO [M + H]+ 342.0296; found
342.0238.
2-Bromo-6-(3,4-dimethoxyphenyl)pyridine (3aj): Compound 3aj was
prepared according to general procedure A by reacting 2,6-di-
bromopyridine (46 mg, 0.2 mmol) with potassium (2,4-dimeth-
oxyphenyl)trifluoroborate (49 mg, 0.2 mmol), sodium carbonate
(85 mg, 0.8 mmol), potassium chloride (7 mg, 0.1 mmol), tri-
phenylphosphine (3.0 mg, 6 mol-%), and tetrakis(triphenylphos-
phine)palladium(0) (7.0 mg, 3 mol-%) in a mixture of degassed tol-
uene/ethanol (1.40:0.35 mL) and degassed water (0.70 mL). The re-
action mixture was stirred at 40 °C for 6 h. After extraction, purifi-
cation of the crude material by preparative TLC (20% EtOAc in
roborate (46 mg, 0.2 mmol), sodium carbonate (85 mg, 0.8 mmol),
potassium chloride (7 mg, 0.1 mmol), triphenylphosphine (3.0 mg,
6 mol-%), and tetrakis(triphenylphosphine)palladium(0) (7.0 mg,
3 mol-%) in a mixture of degassed toluene/ethanol (1.40:0.35 mL)
and degassed water (0.70 mL). The reaction mixture was stirred at
40 °C for 6 h. After extraction, purification of the crude material by
flash chromatography on silica gel (0% to 20% EtOAc in heptane)
afforded 3bc as
a
yellow powder (31 mg, 64%). 1H NMR
(300 MHz, CDCl3): δ = 7.73 (d, J = 8.8 Hz, 2 H), 8.10 (t, J =
2.0 Hz, 1 H), 8.34 (d, J = 8.8 Hz, 2 H), 8.77 (dd, J = 15.7, 2.0 Hz,
2 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 121.6 (C), 124.8 (2
CH), 128.4 (2 CH), 136.4 (C), 138.0 (CH), 142.5 (C), 145.9 (CH),
1
heptane) afforded 3aj as a white powder (28 mg, 47%). H NMR
(300 MHz, CDCl3): δ = 3.86 (s, 3 H), 3.92 (s, 3 H), 6.86 (d, J =
8.3 Hz, 1 H), 7.27 (dd, J = 7.7, 1.0 Hz, 1 H), 7.40–7.50 (m, 2 H), 148.4 (C), 150.4 (CH) ppm. IR (neat): ν = 3109, 3085, 2963, 1511,
˜
7.52–7.57 (m, 2 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 56.2
(CH3), 56.3 (CH3), 110.2 (CH), 111.2 (CH), 118.5 (CH), 119.9
1343, 1259, 1089, 1047, 1015, 790 cm–1. HRMS (ESI): calcd. for
C11H879BrN2O2 [M + H]+ 278.9691; found 278.9761; calcd. for
(CH) 125.8 (CH), 130.8 (C), 139.1 (CH), 142.2 (C), 149.5 (C), 150.7 C11H881BrN2O2 [M + H]+ 280.9670; found 280.9768.
(C), 158.4 (C) ppm. IR (neat): ν = 3001, 2959, 2934, 2835, 1546,
˜
1-Bromo-3-(4-ethoxyphenyl)benzene (3ca): Compound 3ca was pre-
pared according to general procedure A by reacting 1,3-dibromo-
benzene (24 μL, 0.2 mmol) with potassium (4-ethoxyphenyl)tri-
fluoroborate (46 mg, 0.2 mmol), sodium carbonate (85 mg,
0.8 mmol), potassium chloride (7 mg, 0.1 mmol), triphenylphos-
phine (3.0 mg, 6.0 mol-%), and tetrakis(triphenylphosphine)palla-
dium(0) (7.0 mg, 3 mol-%) in a mixture of degassed toluene/ethanol
(1.40:0.35 mL) and degassed water (0.70 mL). The reaction mixture
was stirred at 40 °C for 6 h. After extraction, purification of the
crude material by preparative TLC (20% CH2Cl2 in heptane) af-
1513, 1420, 1254, 1170, 1022, 790 cm–1. HRMS (ESI): calcd. for
C13H1379BrNO2 [M + H]+ 294.0051; found 294.0130; calcd. for
C13H1381BrNO2 [M + H]+ 296.0031; found 296.0112.
3-Bromo-5-(4-ethoxyphenyl)pyridine (3ba): Compound 3ba was pre-
pared according to general procedure A by reacting 3,5-dibromo-
pyridine (46 mg, 0.2 mmol) with potassium (4-ethoxyphenyl)tri-
fluoroborate (46 mg, 0.2 mmol), sodium carbonate (85 mg,
0.8 mmol), potassium chloride (7 mg, 0.1 mmol), triphenylphos-
phine (3.0 mg, 6 mol-%), and tetrakis(triphenylphosphine)palla-
dium(0) (7.0 mg, 3 mol-%) in a mixture of degassed toluene/ethanol
(1.40:0.35 mL) and degassed water (0.70 mL). The reaction mixture
was stirred at 40 °C for 6 h. After extraction, purification of the
crude material by flash chromatography on silica gel (0 to 20%
1
forded 3ca as a white powder (45 mg, 82%). H NMR (300 MHz,
CDCl3): δ = 1.36 (t, J = 7.0 Hz, 3 H), 3.99 (q, J = 7.0 Hz, 2 H),
6.88 (d, J = 8.8 Hz, 2 H), 7.15–7.22 (m, 1 H), 7.30–7.38 (m, 2 H),
7.40 (d, J = 8.8 Hz, 2 H), 7.61 (t, J = 1.9 Hz, 1 H) ppm. 13C NMR
8
www.eurjoc.org
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O40090
/KAP1
Date: 26-03-14 17:30:37
Pages: 15
Selective Suzuki–Miyaura Monocouplings
(75 MHz, CDCl3): δ = 15.1 (CH3), 63.7 (CH2), 115.0 (2 CH), 123.1
1-Bromo-4-(4-methylphenyl)benzene (3db): Compound 3db was pre-
(C), 125.5 (CH), 128.3 (2 CH), 129.7 (CH), 129.9 (CH), 130.4
pared according to general procedure A by reacting 1,4-dibromo-
(CH), 132.2 (C), 143.2 (C), 159.1 (C) ppm. IR (neat): ν = 2977, benzene (47 mg, 0.2 mmol) with potassium (4-methylphenyl)tri-
˜
2929, 1606, 1579, 1469, 1393, 1251, 1188, 1047, 790 cm–1. HRMS
(APPI): calcd. for C14H1379BrO [M]+ 276.0150; found 276.0166;
calcd. for C14H1381BrO [M]+ 278.0129; found 278.0147.
fluoroborate (40 mg, 0.2 mmol), sodium carbonate (85 mg,
0.8 mmol), potassium chloride (7 mg, 0.1 mmol), triphenylphos-
phine (3.0 mg, 6 mol-%), and tetrakis(triphenylphosphine)palla-
dium(0) (7.0 mg, 3 mol-%) in a mixture of degassed toluene/ethanol
(1.40:0.35 mL) and degassed water (0.70 mL). The reaction mixture
was stirred at 40 °C for 6 h. After extraction, purification of the
crude material by preparative TLC (20% CH2Cl2 in heptane) af-
1-Bromo-3-(4-methylphenyl)benzene (3cb): Compound 3cb was pre-
pared according to general procedure A by reacting 1,3-dibromo-
benzene (24 μL, 0.2 mmol) with potassium (4-methylphenyl)tri-
fluoroborate (40 mg, 0.2 mmol), sodium carbonate (85 mg,
0.8 mmol), potassium chloride (7 mg, 0.1 mmol), triphenylphos-
phine (3.0 mg, 6 mol-%), and tetrakis(triphenylphosphine)palla-
dium(0) (7.0 mg, 3 mol-%) in a mixture of degassed toluene/ethanol
(1.40:0.35 mL) and degassed water (0.70 mL). The reaction mixture
was stirred at 40 °C for 6 h. After extraction, purification of the
crude material by preparative TLC (20% CH2Cl2 in heptane) af-
1
forded 3db as a white powder (36 mg, 73%). H NMR (300 MHz,
CDCl3): δ = 2.37 (s, 3 H), 7.23 (d, J = 8.2 Hz, 2 H), 7.42 (d, J =
8.6 Hz, 2 H), 7.43 (d, J = 8.2 Hz, 2 H), 7.52 (d, J = 8.6 Hz, 2 H)
ppm. 13C NMR (75 MHz, CDCl3): δ = 21.3 (CH3), 121.4 (C), 127.0
(2 CH), 128.8 (2 CH), 129.7 (C), 140.3 (C), 129.8 (2 CH), 132.0 (2
CH), 137.7 (C) ppm. IR (neat): ν = 3030, 2855, 1555, 1462, 1450,
˜
1
1025, 821, 790 cm–1. HRMS (APPI): calcd. for C13H1179Br [M]+
246.0044; found 246.0064; calcd. for C13H1181Br [M]+ 248.0024;
found 248.0044.
forded 3cb as a beige powder (38 mg, 77%). H NMR (300 MHz,
CDCl3): δ = 2.37 (s, 3 H), 7.19–7.25 (m, 2 H), 7.27 (d, J = 7.9 Hz,
1 H), 7.39–7.44 (m, 3 H), 7.45–7.49 (m, 1 H), 7.69 (t, J = 1.9 Hz,
1 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 21.3 (CH3), 123.1 (C),
125.7 (CH), 127.1 (2 CH), 129.8 (2 CH), 130.1 (CH), 130.2 (CH),
1-Bromo-4-(4-nitrophenyl)benzene (3dc): Compound 3dc was pre-
pared according to general procedure A by reacting 1,4-dibromo-
benzene (47 mg, 0.2 mmol) with potassium (4-nitrophenyl)tri-
fluoroborate (46 mg, 0.2 mmol), sodium carbonate (85 mg,
0.8 mmol), potassium chloride (7 mg, 0.1 mmol), triphenylphos-
phine (3.0 mg, 6 mol-%), and tetrakis(triphenylphosphine)palla-
dium(0) (7.0 mg, 3 mol-%) in a mixture of degassed toluene/ethanol
(1.40:0.35 mL) and degassed water (0.70 mL). The reaction mixture
was stirred at 40 °C for 6 h. After extraction, purification of the
crude material by preparative TLC (20% CH2Cl2 in heptane) af-
130.4 (CH), 137.0 (C), 138.0 (C), 143.5 (C) ppm. IR (neat): ν =
˜
3032, 2857, 1555, 1467, 1450, 1030, 822, 790 cm–1. HRMS (APPI):
calcd. for C13H1179Br [M]+ 246.0044; found 246.0032; calcd. for
C13H1181Br [M]+ 248.0024; found 248.0013.
1-Bromo-3-(4-nitrophenyl)benzene (3cc): Compound 3cc was pre-
pared according to general procedure A by reacting 1,3-dibromo-
benzene (24 μL, 0.2 mmol) with potassium (4-nitrophenyl)tri-
fluoroborate (46 mg, 0.2 mmol), sodium carbonate (85 mg,
0.8 mmol), potassium chloride (7 mg, 0.1 mmol), triphenylphos-
phine (3.0 mg, 6 mol-%), and tetrakis(triphenylphosphine)palla-
dium(0) (7.0 mg, 3 mol-%) in a mixture of degassed toluene/ethanol
(1.40:0.35 mL) and degassed water (0.70 mL). The reaction mixture
was stirred at 40 °C for 6 h. After extraction, purification of the
crude material by preparative TLC (20% CH2Cl2 in heptane) af-
1
forded 3dc as a beige powder (30 mg, 55%). H NMR (300 MHz,
CDCl3): δ = 7.47 (d, J = 8.8 Hz, 2 H), 7.61 (d, J = 8.8 Hz, 2 H),
7.69 (d, J = 8.8 Hz, 2 H), 8.28 (d, J = 8.8 Hz, 2 H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 123.7 (C), 124.5 (2 CH), 127.9 (2 CH), 129.1
(2 CH), 132.6 (2 CH), 137.9 (C), 146.6 (C), 147.5 (C) ppm. IR
(neat): ν = 2998, 2951, 1509, 1406, 1394, 1346, 1245, 1074, 1056,
˜
1
871 cm–1. MS: no ionization could be observed for this compound.
forded 3cc as a beige powder (26 mg, 47%). H NMR (300 MHz,
CDCl3): δ = 7.35 (dd, J = 7.9, 7.6 Hz, 1 H), 7.49–7.59 (m, 2 H),
7.69 (d, J = 8.8 Hz, 2 H), 7.75 (t, J = 1.8 Hz, 1 H), 8.29 (d, J =
8.8 Hz, 2 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 123.5 (C),
124.4 (2 CH), 126.2 (CH), 128.1 (2 CH), 130.7 (CH), 130.9 (CH),
1-Bromo-2-(4-ethoxyphenyl)benzene (3ea): Compound 3ea was pre-
pared according to general procedure A by reacting 1,2-dibromo-
benzene (24 μL, 0.2 mmol) with potassium (4-ethoxyphenyl)tri-
fluoroborate (46 mg, 0.2 mmol), sodium carbonate (85 mg,
0.8 mmol), potassium chloride (7 mg, 0.1 mmol), triphenylphos-
phine (3.0 mg, 6 mol-%), and tetrakis(triphenylphosphine)palla-
dium(0) (7.0 mg, 3 mol-%) in a mixture of degassed toluene/ethanol
(1.40:0.35 mL) and degassed water (0.70 mL). The reaction mixture
was stirred at 100 °C for 6 h. After extraction, purification of the
crude material by preparative TLC (10% EtOAc in heptane) af-
131.6 (C), 132.1 (CH), 141.1 (C), 146.2 (C) ppm. IR (neat): ν =
˜
2988, 2901, 1511, 1406, 1394, 1343, 1242, 1074, 1056, 854 cm–1.
MS: no ionization could be observed for this compound.
1-Bromo-4-(4-ethoxyphenyl)benzene (3da): Compound 3da was pre-
pared according to general procedure A by reacting 1,4-dibromo-
benzene (47 mg, 0.2 mmol) with potassium (4-ethoxyphenyl)tri-
fluoroborate (46 mg, 0.2 mmol), sodium carbonate (85 mg,
0.8 mmol), potassium chloride (7 mg, 0.1 mmol), triphenylphos-
phine (3.0 mg, 6 mol-%), and tetrakis(triphenylphosphine)palla-
dium(0) (7.0 mg, 3 mol-%) in a mixture of degassed toluene/ethanol
(1.40:0.35 mL) and degassed water (0.70 mL). The reaction mixture
was stirred at 40 °C for 6 h. After extraction, purification of the
crude material by preparative TLC (20% CH2Cl2 in heptane) af-
1
forded 3ea as a white powder (41 mg, 74%). H NMR (300 MHz,
CDCl3): δ = 1.43 (t, J = 7.0 Hz, 3 H), 4.07 (q, J = 7.0 Hz, 2 H),
6.94 (d, J = 8.7 Hz, 2 H), 7.10–7.20 (m, 1 H), 7.27–7.31 (m, 2 H),
7.32 (d, J = 8.7 Hz, 2 H), 7.64 (d, J = 8.2 Hz, 1 H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 15.1 (CH3), 63.7 (CH2), 114.1 (2 CH), 123.1
(C), 127.5 (CH), 128.6 (CH), 130.7 (2 CH), 131.6 (CH), 133.3
(CH), 133.6 (C), 142.5 (C), 158.7 (C) ppm. IR (neat): ν = 2971,
˜
1
forded 3da as a white powder (42 mg, 76%). H NMR (300 MHz,
2925, 1601, 1570, 1469, 1393, 1251, 1181, 1044, 790 cm–1. HRMS
(APPI): calcd. for C14H1378BrO [M]+ 276.0150; found 276.0135;
calcd. for C14H1381BrO [M]+ 278.0129; found 278.0115.
CDCl3): δ = 1.43 (t, J = 7.0 Hz, 3 H), 4.06 (q, J = 7.0 Hz, 2 H),
6.95 (d, J = 8.6 Hz, 2 H), 7.39 (d, J = 8.6 Hz, 2 H), 7.46 (d, J =
8.6 Hz, 2 H), 7.51 (d, J = 8.6 Hz, 2 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 14.9 (CH3), 63.6 (CH2), 114.9 (2 CH), 120.7 (C), 127.7 1-Bromo-2-(4-methylphenyl)benzene (3eb): Compound 3eb was pre-
(C), 128.0 (2 CH), 128.3 (2 CH), 131.8 (2 CH), 139.8 (C), 158.8
pared according to general procedure A by reacting 1,2-dibromo-
benzene (24 μL, 0.2 mmol) with potassium (4-methylphenyl)tri-
fluoroborate (40 mg, 0.2 mmol), sodium carbonate (85 mg,
0.8 mmol), potassium chloride (7 mg, 0.1 mmol), triphenylphos-
phine (3.0 mg, 6 mol-%), and tetrakis(triphenylphosphine)palla-
(C) ppm. IR (neat): ν = 2980, 2929, 1738, 1604, 1475, 1390, 1283,
˜
1248, 1197, 1045, 815, 800 cm–1. HRMS (APPI): calcd. for
C14H1379BrO [M]+ 276.0150; found 276.0134; calcd. for
C14H1381BrO [M]+ 278.0129; found 278.0115.
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
9

Job/Unit: O40090
/KAP1
Date: 26-03-14 17:30:37
Pages: 15
C. Minard, C. Palacio, K. Cariou, R. H. Dodd
FULL PAPER
dium(0) (7.0 mg, 3 mol-%) in a mixture of degassed toluene/ethanol
(1.40:0.35 mL) and degassed water (0.70 mL). The reaction mixture
was stirred at 100 °C for 6 h. After extraction, purification of the
crude material by preparative TLC (4% CH2Cl2 in heptane) af-
2.35 (s, 3 H), 7.00 (br s, 2 H), 7.16 (d, J = 8.1 Hz, 2 H), 7.39 (d, J
= 8.1 Hz, 2 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 21.4 (CH3),
110.9 (C), 122.9 (CH), 125.7 (2 CH), 129.9 (2 CH), 130.9 (CH),
131.1 (C), 138.1 (C), 146.3 (C) ppm. IR (neat): ν = 2994, 1510,
˜
1441, 1394, 1074, 1045 cm–1. HRMS (APPI): calcd. for C11H979BrS
[M]+ 251.9608; found 251.9637; calcd. for C11H981BrS [M]+
253.9598; found 253.9616.
1
forded 3eb as a white powder (20 mg, 40%). H NMR (300 MHz,
CDCl3): δ = 2.44 (s, 3 H), 7.17–7.24 (m, 1 H), 7.27–7.30 (m, 1 H),
7.31–7.41 (m, 4 H), 7.69 (d, J = 8.0 Hz, 2 H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 21.5 (CH3), 122.9 (C), 127.5 (CH), 128.7
(CH), 128.9 (2 CH), 129.5 (2 CH), 131.5 (CH), 133.3 (CH), 137.6
2-Bromo-5-(4-fluorophenyl)thiophene (3fd): Compound 3fd was pre-
pared according to general procedure A by reacting 2,5-dibromo-
thiophene (23 μL, 0.2 mmol) with potassium (4-fluorophenyl)tri-
fluoroborate (40 mg, 0.2 mmol), sodium carbonate (85 mg,
0.8 mmol), potassium chloride (7 mg, 0.1 mmol), triphenylphos-
phine (3.0 mg, 6 mol-%), and tetrakis(triphenylphosphine)palla-
dium(0) (7.0 mg, 3 mol-%) in a mixture of degassed toluene/ethanol
(1.40:0.35 mL) and degassed water (0.70 mL). The reaction mixture
was stirred at 70 °C overnight. After extraction, purification of the
crude material by preparative TLC (2% MTBE in heptane) af-
(C), 138.4 (C), 142.8 (C) ppm. IR (neat): ν = 3029, 2847, 1551,
˜
1459, 1450, 1025, 817, 790 cm–1. HRMS (APPI): calcd. for
C13H1178Br [M]+ 246.0044; found 246.0036; calcd. for C13H1181Br
[M]+ 248.0024; found 248.0017.
1-Bromo-2-(4-nitrophenyl)benzene (3ec): Compound 3ec was pre-
pared according to general procedure A by reacting 1,2-dibromo-
benzene (24 μL, 0.2 mmol) with potassium (4-nitrophenyl)tri-
fluoroborate (46 mg, 0.2 mmol), sodium carbonate (85 mg,
0.8 mmol), potassium chloride (7 mg, 0.1 mmol), triphenylphos-
phine (3.0 mg, 6 mol-%), and tetrakis(triphenylphosphine)palla-
dium(0) (7.0 mg, 3 mol-%) in a mixture of degassed toluene/ethanol
(1.40:0.35 mL) and degassed water (0.70 mL). The reaction mixture
was stirred at 100 °C for 6 h. After extraction, purification of the
crude material by preparative TLC (10% EtOAc in heptane) in
heptane afforded 3ec as a white powder (27 mg, 49%). 1H NMR
1
forded 3fd as a white powder (23 mg, 45%). H NMR (300 MHz,
CDCl3): δ = 6.89–7.19 (m, 4 H), 7.39–7.60 (m, 2 H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 111.3 (C), 116.1 (d, J = 21.8 Hz, 2 CH),
123.5 (CH), 127.4 (d, J = 8.1 Hz, 2 CH), 130.0 (d, J = 3.2 Hz, C),
131.1 (CH), 145.0 (C), 162.5 (d, J = 246.5 Hz, C) ppm. IR (neat):
ν = 3082, 1613, 1381, 1394, 1170, 1037, 865 cm–1. HRMS (APPI):
˜
calcd. for C10H679BrFS [M]+ 255.9358; found 255.9386; calcd. for
(300 MHz, CDCl3): δ = 7.25–7.34 (m, 2 H), 7.40 (ddd, J = 8.0, 6.8, C10H681BrFS [M]+ 257.9364; found 257.9337.
1.1 Hz, 1 H), 7.57 (d, J = 8.8 Hz, 2 H), 7.69 [dd, (d, J = 8.0, 1.1 Hz,
4-(4-Ethoxyphenyl)phenyl Trifluoromethanesulfonate (7aa): Com-
pound 7aa was prepared according to general procedure A by re-
acting 1,4-bis(trifluoromethylsulfonyloxy)benzene (75 mg,
1 H)], 8.28 (d, J = 8.8 Hz, 2 H) ppm. 13C NMR (75 MHz, CDCl3):
δ = 122.0 (C), 123.3 (2 CH), 127.7 (CH), 129.9 (CH), 130.5 (2 CH),
130.9 (CH), 133.5 (CH), 140.4 (C), 147.5 (C), 153.5 (C) ppm. IR
0.2 mmol) with potassium (4-ethoxyphenyl)trifluoroborate (46 mg,
0.2 mmol), sodium carbonate (85 mg, 0.8 mmol), potassium chlor-
ide (7 mg, 0.1 mmol), triphenylphosphine (3.0 mg, 6 mol-%), and
tetrakis(triphenylphosphine)palladium(0) (7.0 mg, 3 mol-%) in a
mixture of degassed toluene/ethanol (1.40:0.35 mL) and degassed
water (0.70 mL). The reaction mixture was stirred at 40 °C for 6 h.
After extraction, purification of the crude material by preparative
TLC (20% CH2Cl2 in heptane) afforded 7aa as a white powder
(64 mg, 93%). 1H NMR (300 MHz, CDCl3): δ = 1.43 (t, J = 7.0 Hz,
3 H), 4.07 (q, J = 7.0 Hz, 2 H), 6.96 (d, J = 8.8 Hz, 2 H), 7.29 (d,
J = 8.8 Hz, 2 H), 7.46 (d, J = 8.9 Hz, 2 H), 7.58 (d, J = 8.9 Hz, 2
H) ppm. 13C NMR (75 MHz, CDCl3): δ = 15.0 (CH3), 63.8 (CH2),
115.2 (2 CH), 119.1 (q, J = 321.3 Hz, CF3), 121.8 (2 CH), 128.4 (2
CH), 128.5 (2 CH), 131.8 (C), 141.6 (C), 148.7 (C), 159.3 (C) ppm.
(neat): ν = 2985, 2888, 1509, 1401, 1394, 1340, 1242, 1074, 1045,
˜
844 cm–1. MS: no ionization could be observed for this compound.
2-Bromo-5-(4-ethoxyphenyl)thiophene (3fa): Compound 3fa was
prepared according to general procedure A by reacting 2,5-di-
bromothiophene (23 μL, 0.2 mmol) with potassium (4-ethoxy-
phenyl)trifluoroborate (69 mg, 0.3 mmol), sodium carbonate
(85 mg, 0.8 mmol), potassium chloride (7 mg, 0.1 mmol), tri-
phenylphosphine (3.0 mg, 6 mol-%), and tetrakis(triphenylphos-
phine)palladium(0) (7.0 mg, 3 mol-%) in a mixture of degassed tol-
uene/ethanol (1.40:0.35 mL) and degassed water (0.70 mL). The re-
action mixture was stirred at 70 °C overnight. After extraction, pu-
rification of the crude material by flash chromatography on neutral
alumina gel [2% methyl tert-butyl ether (MTBE) in heptane] af-
1
forded 3fa as a white powder (30 mg, 53%). H NMR (300 MHz,
IR (neat): ν = 2988, 2902, 1604, 1491, 1422, 1394, 1209, 1150, 1044,
˜
CDCl3): δ = 1.41 (t, J = 7.0 Hz, 3 H), 4.03 (q, J = 7.0 Hz, 2 H),
817 cm–1. HRMS (APPI): calcd. for C15H13F3O4S [M]+ 346.0487;
6.84–6.92 (m, 3 H), 6.97 (d, J = 3.9 Hz, 1 H), 7.40 (d, J = 9.0 Hz, found 346.0469.
2 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 15.0 (CH3), 63.8
(CH2), 110.3 (C), 115.2 (2 CH), 122.3 (CH), 126.6 (C), 127.2 (2
4-(4-Methylphenyl)phenyl Trifluoromethanesulfonate (7ab): Com-
pound 7ab was prepared according to general procedure A by
reacting 1,4-bis(trifluoromethylsulfonyloxy)benzene (75 mg,
CH), 130.9 (CH), 146.1 (C), 159.1 (C) ppm. IR (neat): ν = 2997,
˜
2896, 1618, 1400, 1254, 1164, 1015 cm–1. HRMS (APPI): calcd. for
C12H1179BrOS [M]+ 281.9714; found 281.9732; calcd. for
C12H1181BrOS [M]+ 283.9694; found 283.9711.
0.2 mmol) with potassium (4-methylphenyl)trifluoroborate (40 mg,
0.2 mmol), sodium carbonate (85 mg, 0.8 mmol), potassium chlor-
ide (7 mg, 0.1 mmol), triphenylphosphine (3.0 mg, 6 mol-%), and
tetrakis(triphenylphosphine)palladium(0) (7.0 mg, 3 mol-%) in a
mixture of degassed toluene/ethanol (1.40:0.35 mL) and degassed
water (0.70 mL). The reaction mixture was stirred at 40 °C for 6 h.
After extraction, purification of the crude material by preparative
TLC (0 to 20% CH2Cl2 in heptane) afforded 7ab as a white powder
(44 mg, 69%). 1H NMR (300 MHz, CDCl3): δ = 2.40 (s, 3 H),
7.24–7.27 (m, 2 H), 7.34 (d, J = 8.8 Hz, 2 H), 7.47 (d, J = 8.2 Hz,
2 H), 7.64 (d, J = 8.8 Hz, 2 H) ppm. 13C NMR (75 MHz, CDCl3):
δ = 21.1 (CH3), 118.9 (q, J = 321.0 Hz, CF3), 121.6 (2 CH), 127.0
(2 CH), 128.6 (2 CH), 129.7 (2 CH), 136.4 (C), 138.0 (C), 141.6
2-Bromo-5-(4-methylphenyl)thiophene (3fb): Compound 3fb was
prepared according to general procedure A by reacting 2,5-di-
bromothiophene (23 μL, 0.2 mmol) with potassium (4-methylphen-
yl)trifluoroborate (60 mg, 0.3 mmol), sodium carbonate (85 mg,
0.8 mmol), potassium chloride (7 mg, 0.1 mmol), triphenylphos-
phine (3.0 mg, 6 mol-%), and tetrakis(triphenylphosphine)palla-
dium(0) (7.0 mg, 3 mol-%) in a mixture of degassed toluene/ethanol
(1.40:0.35 mL) and degassed water (0.70 mL). The reaction mixture
was stirred at 70 °C overnight. After extraction, purification of the
crude material by preparative TLC (100% heptane) afforded 3fb as
1
a white powder (23 mg, 45%). H NMR (300 MHz, CDCl3): δ =
(C), 148.7 (C) ppm. IR (neat): ν = 2930, 1493, 1425, 1190, 1050,
˜
10
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© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O40090
/KAP1
Date: 26-03-14 17:30:37
Pages: 15
Selective Suzuki–Miyaura Monocouplings
810 cm–1. HRMS (APPI): calcd. for C14H11F3O3S [M]+ 316.0381;
found 316.0369.
acting
1,2-bis(trifluoromethylsulfonyloxy)benzene
(75 mg,
0.2 mmol) with potassium (4-ethoxyphenyl)trifluoroborate (46 mg,
0.2 mmol), sodium carbonate (85 mg, 0.8 mmol), potassium chlor-
ide (7 mg, 0.1 mmol), triphenylphosphine (3.0 mg, 6 mol-%), and
tetrakis(triphenylphosphine)palladium(0) (7.0 mg, 3 mol-%) in a
mixture of degassed toluene/ethanol (1.40:0.35 mL) and degassed
water (0.70 mL). The reaction mixture was stirred at 70 °C over-
night. After extraction, purification of the crude material by pre-
parative TLC (0 to 20% CH2Cl2 in heptane) afforded 7ca as a white
3-(4-Ethoxyphenyl)phenyl Trifluoromethanesulfonate (7ba): Com-
pound 7ba was prepared according to general procedure A by re-
acting
1,3-bis(trifluoromethylsulfonyloxy)benzene
(75 mg,
0.2 mmol) with potassium (4-ethoxyphenyl)trifluoroborate (46 mg,
0.2 mmol), sodium carbonate (85 mg, 0.8 mmol), potassium chlor-
ide (7 mg, 0.1 mmol), triphenylphosphine (3.0 mg, 6 mol-%), and
tetrakis(triphenylphosphine)palladium(0) (7.0 mg, 3 mol-%) in a
mixture of degassed toluene/ethanol (1.40:0.35 mL) and degassed
water (0.70 mL). The reaction mixture was stirred at 70 °C over-
night. After extraction, purification of the crude material by pre-
parative TLC (0 to 20% CH2Cl2 in heptane) afforded 7ba as a
white powder (54 mg, 78%). 1H NMR (300 MHz, CDCl3): δ = 1.43
(t, J = 7.0 Hz, 3 H), 4.07 (q, J = 7.0 Hz, 2 H), 6.97 (d, J = 8.9 Hz,
2 H), 7.18 (ddd, J = 8.0, 2.3, 1.0 Hz, 1 H), 7.40–7.44 (m, 1 H), 7.48
(d, J = 8.9 Hz, 2 H), 7.44–7.49 (m, 1 H), 7.52–7.58 (m, 1 H) ppm.
13C NMR (75 MHz, CDCl3): δ = 15.0 (CH3), 63.8 (CH2), 115.2 (2
CH), 119.0 (q, J = 320.3 Hz, CF3), 119.3 (CH), 119.6 (CH), 126.7
(CH), 128.4 (2 CH), 130.6 (CH), 131.5 (C), 143.8 (C), 150.3 (C),
1
powder (45 mg, 65%). H NMR (300 MHz, CDCl3): δ = 1.36 (t, J
= 7.0 Hz, 3 H), 4.00 (q, J = 7.0 Hz, 2 H), 6.89 (d, J = 8.8 Hz, 2
H), 7.28–7.54 (m, 6 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 15.0
(CH3), 63.7 (CH2), 114.7 (2 CH), 118.6 (q, J = 321.2 Hz, CF3),
122.3 (CH), 128.0 (C), 128.6 (CH), 128.7 (CH), 130.7 (2 CH), 132.1
(CH), 135.5 (C), 147.1 (C), 159.3 (C) ppm. IR (neat): ν = 2990,
˜
2888, 1614, 1495, 1422, 1397, 1209, 1162, 1056, 877 cm–1. HRMS
(APPI): calcd. for C15H13F3O4S [M]+ 346.0487; found 346.0481.
2-(4-Methylphenyl)phenyl Trifluoromethanesulfonate (7cb): Com-
pound 7cb was prepared according to general procedure A by re-
acting
1,2-bis(trifluoromethylsulfonyloxy)benzene
(75 mg,
159.5 (C) ppm. IR (neat): ν = 2988, 2902, 1604, 1491, 1422, 1394,
˜
0.2 mmol) with potassium (4-methylphenyl)trifluoroborate (40 mg,
0.2 mmol), sodium carbonate (85 mg, 0.8 mmol), potassium chlor-
ide (7 mg, 0.1 mmol), triphenylphosphine (3.0 mg, 6 mol-%), and
tetrakis(triphenylphosphine)palladium(0) (7.0 mg, 3 mol-%) in a
mixture of degassed toluene/ethanol (1.40:0.35 mL) and degassed
water (0.70 mL). The reaction mixture was stirred at 70 °C over-
night. After extraction, purification of the crude material by flash
column chromatography on silica gel (2% EtOAc in heptane) af-
1209, 1150, 1044, 817 cm–1. HRMS (APPI): calcd. for
C15H13F3O4S [M]+ 346.0487; found 346.0473.
3-(4-Methylphenyl)phenyl Trifluoromethanesulfonate (7bb): Com-
pound 7bb was prepared according to general procedure A by re-
acting
1,3-bis(trifluoromethylsulfonyloxy)benzene
(75 mg,
0.2 mmol) with potassium (4-methylphenyl)trifluoroborate (40 mg,
0.2 mmol), sodium carbonate (85 mg, 0.8 mmol), potassium chlor-
ide (7 mg, 0.1 mmol), triphenylphosphine (3.0 mg, 6 mol-%), and
tetrakis(triphenylphosphine)palladium(0) (7.0 mg, 3 mol-%) in a
mixture of degassed toluene/ethanol (1.40:0.35 mL) and degassed
water (0.70 mL). The reaction mixture was stirred at 70 °C over-
night. After extraction, purification of the crude material by pre-
parative TLC (20% CH2Cl2 in heptane) afforded 7bb as a white
1
forded 7cb as a white powder (41 mg, 62%). H NMR (300 MHz,
CDCl3): δ = 2.33 (s, 3 H), 7.18 (d, J = 7.5 Hz, 2 H), 7.23–7.43 (m,
6 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 21.3 (CH3), 118.4 (q,
J = 320.2 Hz, CF3), 122.0 (CH), 128.5 (CH), 128.7 (CH), 129.2 (4
CH), 132.0 (CH), 132.7 (C), 135.6 (C), 138.2 (C), 146.9 (C) ppm.
IR (neat): ν = 2990, 2888, 1614, 1495, 1422, 1397, 1209, 1162, 1056,
˜
1
877 cm–1. HRMS (APPI): calcd. for C14H11F3O3S [M]+ 316.0381;
found 316.0372.
powder (44 mg, 70%). H NMR (300 MHz, CDCl3): δ = 2.31 (s, 3
H), 7.09–7.16 (m, 1 H), 7.19 (d, J = 7.8 Hz, 2 H), 7.32–7.46 (m, 4
H) 7.46–7.54 (m, 1 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 21.3
(CH3), 119.0 (q, J = 318 Hz, CF3), 119.7 (CH), 119.9 (CH), 127.0
(CH), 127.2 (2 CH), 130.0 (2 CH), 130.6 (CH), 136.4 (C), 138.6
2-(4-Nitrophenyl)phenyl Trifluoromethanesulfonate (7cc): Com-
pound 7cc was prepared according to general procedure A by re-
acting
1,2-bis(trifluoromethylsulfonyloxy)benzene
(75 mg,
(C), 144.2 (C), 150.3 (C) ppm. IR (neat): ν = 2945, 2855, 1598,
˜
1530, 1417, 1345, 1212, 1126 cm–1. HRMS (APPI): calcd. for
C14H11F3O3S [M]+ 316.0381; found 316.0372.
0.2 mmol) with potassium (4-nitrophenyl)trifluoroborate (46 mg,
0.2 mmol), sodium carbonate (85 mg, 0.8 mmol), potassium chlor-
ide (7 mg, 0.1 mmol), triphenylphosphine (3.0 mg, 6 mol-%), and
tetrakis(triphenylphosphine)palladium(0) (7.0 mg, 3 mol-%) in a
mixture of degassed toluene/ethanol (1.40:0.35 mL) and degassed
water (0.70 mL). The reaction mixture was stirred at 70 °C over-
night. After extraction, purification of the crude material by pre-
parative TLC (0 to 20% CH2Cl2 in heptane) afforded 7cc as a white
powder (25 mg, 38%). 1H NMR (300 MHz, CDCl3): δ = 7.39–7.56
(m, 4 H), 7.63 (d, J = 8.9 Hz, 2 H), 8.31 (d, J = 8.9 Hz, 2 H) ppm.
13C NMR (75 MHz, CDCl3): δ = 118.3 (q, J = 321.0 Hz, CF3),
122.7 (CH), 124.0 (2 CH), 129.1 (CH), 130.6 (2 CH), 130.7 (CH),
131.9 (CH), 133.6 (C), 142.4 (C), 146.6 (C), 147.9 (C) ppm. IR
3-(4-Nitrophenyl)phenyl Trifluoromethanesulfonate (7bc): Com-
pound 7bc was prepared according to general procedure A by re-
acting
1,3-bis(trifluoromethylsulfonyloxy)benzene
(75 mg,
0.2 mmol) with potassium (4-nitrophenyl)trifluoroborate (46 mg,
0.2 mmol), sodium carbonate (85 mg, 0.8 mmol), potassium chlor-
ide (7 mg, 0.1 mmol), triphenylphosphine (3.0 mg, 6 mol-%), and
tetrakis(triphenylphosphine)palladium(0) (7.0 mg, 3 mol-%) in a
mixture of degassed toluene/ethanol (1.40:0.35 mL) and degassed
water (0.70 mL). The reaction mixture was stirred at 70 °C over-
night. After extraction, purification of the crude material by pre-
parative TLC (20% CH2Cl2 in heptane) afforded 7bc as a white
powder (39 mg, 57%). 1H NMR (300 MHz, CDCl3): δ = 7.30–7.40
(m, 1 H), 7.50 (t, J = 1.9 Hz, 1 H), 7.54–7.67 (m, 2 H), 7.71 (d, J
= 8.9 Hz, 2 H), 8.32 (d, J = 8.9 Hz, 2 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 119.0 (q, J = 319.4 Hz, CF3), 120.6 (CH), 121.7 (CH),
124.6 (2 CH), 127.6 (CH), 128.3 (2 CH), 131.3 (CH), 141.7 (C),
(neat): ν = 2922, 2871, 1613, 1487, 1415, 1249, 1212, 1143,
˜
1128 cm–1. MS: no ionization could be observed for this com-
pound.
Diethyl
N-Benzyl-3-(4-ethoxyphenyl)-4-(trifluoromethylsulfonyl-
oxy)pyrrole-2,5-dicarboxylate (7da): Compound 7da was prepared
according to general procedure A by reacting pyrrole 6d (120 mg,
0.2 mmol) with potassium (4-ethoxyphenyl)trifluoroborate (46 mg,
0.2 mmol), sodium carbonate (85 mg, 0.8 mmol), potassium chlor-
ide (7 mg, 0.1 mmol), triphenylphosphine (3.0 mg, 6 mol-%), and
tetrakis(triphenylphosphine)palladium(0) (7.0 mg, 3 mol-%) in a
145.4 (C), 148.0 (C), 150.3 (C) ppm. IR (neat): ν = 2925, 2865,
˜
1613, 1481, 1421, 1244, 1200, 1139, 1126 cm–1. MS: no ionization
could be observed for this compound.
2-(4-Ethoxyphenyl)phenyl Trifluoromethanesulfonate (7ca): Com-
pound 7ca was prepared according to general procedure A by re-
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
11

Job/Unit: O40090
/KAP1
Date: 26-03-14 17:30:37
Pages: 15
C. Minard, C. Palacio, K. Cariou, R. H. Dodd
2-(4-Fluorophenyl)-6-(4-ethoxyphenyl)pyridine (8): Compound
was prepared according to general procedure B by reacting 2,6-
dibromopyridine (46 mg, 0.2 mmol) with potassium (4-ethoxy-
phenyl)trifluoroborate (46 mg, 0.2 mmol), sodium carbonate
(170 mg, 1.6 mmol), potassium chloride (7 mg, 0.1 mmol), tri-
phenylphosphine (3.0 mg, 6 mol-%), and tetrakis(triphenylphos-
phine)palladium(0) (7.0 mg, 3 mol-%) in a mixture of degassed tol-
uene/ethanol (1.40:0.35 mL) and degassed water (0.70 mL). The re-
action mixture was first stirred at 40 °C for 6 h. Potassium (4-
FULL PAPER
mixture of degassed toluene/ethanol (1.40:0.35 mL) and degassed
water (0.70 mL). The reaction mixture was stirred at 70 °C over-
night. After extraction, purification of the crude material by flash
column chromatography on neutral alumina gel (2% EtOAc in
8
1
heptane) afforded 7da as a white powder (58 mg, 51%). H NMR
(300 MHz, CDCl3): δ = 0.93 (t, J = 6.9 Hz, 3 H), 1.32 (t, J =
7.2 Hz, 3 H), 1.41 (t, J = 7.2 Hz, 3 H), 3.98–4.09 (m, 4 H), 4.34 (q,
J = 6.9 Hz, 2 H), 6.08 (s, 2 H), 6.88 (d, J = 8.7 Hz, 2 H), 7.00 (d,
J = 6.6 Hz, 2 H), 7.16–7.31 (m, 5 H) ppm. 13C NMR (125 MHz,
CDCl3): δ = 13.6 (CH3), 13.9 (CH3), 14.8 (CH3), 49.8 (CH2), 61.2 fluorophenyl)trifluoroborate (40 mg, 0.2 mmol) was then added at
(CH2), 61.7 (CH2), 63.5 (CH2), 113.9 (2 CH), 118.0 (q, J = room temp., and the mixture was heated at 100 °C for 2 h. After
317.0 Hz, CF3), 118.3 (C), 121.9 (C), 123.3 (2 C), 126.2 (2 CH), filtration through silica, chromatography of the crude reaction
127.3 (CH), 128.4 (2 CH), 131.5 (2 CH), 136.1 (C), 137.7 (C), 158.9
product on silica with 0 to 20% EtOAc in heptane afforded 8
(49.0 mg, 83%). 1H NMR (300 MHz, CDCl3): δ = 1.37 (t, J =
7.1 Hz, 3 H), 4.02 (q, J = 7.1 Hz, 2 H), 6.92 (d, J = 8.9 Hz, 2 H),
7.09 (t, J = 8.1 Hz, 2 H), 7.55–7.48 (m, 2 H), 7.68 (t, J = 8.1 Hz,
1 H), 8.00 (d, J = 8.9 Hz, 2 H), 8.08–8.03 (m, 2 H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 14.8 (CH3), 63.6 (CH2), 114.6 (2 CH), 115.5
(d, J = 21.2 Hz, 2 CH), 117.5 (CH), 117.8 (CH), 128.2 (2 CH),
128.7 (d, J = 8.3 Hz, 2 CH), 131.8 (C), 135.8 (d, J = 2.8 Hz, C),
137.4 (CH), 155.6 (C), 156.6 (C), 159.9 (C), 163.5 (d, J = 246.5 Hz,
(C), 159.1 (C), 160.6 (C) ppm. IR (neat): ν = 2983, 1721, 1556,
˜
1425, 1286, 1243, 1185, 1135, 1022, 921, 829, 731 cm–1. HRMS
(ESI): calcd. for C26H27F3NO8S[M
570.1433.
+
H]+ 570.1409; found
Diethyl
N-Benzyl-3-(4-methylphenyl)-4-(trifluoromethylsulfonyl-
oxy)pyrrole-2,5-dicarboxylate (7db): Compound 7db was prepared
according to general procedure A by reacting pyrrole 6d (120 mg,
0.2 mmol) with potassium (4-methylphenyl)trifluoroborate (40 mg,
0.2 mmol), sodium carbonate (85 mg, 0.8 mmol), potassium chlor-
ide (7 mg, 0.1 mmol), triphenylphosphine (3.0 mg, 6 mol-%), and
tetrakis(triphenylphosphine)palladium(0) (7.0 mg, 3 mol-%) in a
mixture of degassed toluene/ethanol (1.40:0.35 mL) and degassed
water (0.70 mL). The reaction mixture was stirred at 70 °C over-
night. After extraction, purification of the crude material by flash
column chromatography on neutral alumina gel (30% CH2Cl2 in
C) ppm. IR (neat): ν = 2940, 1515, 1413, 1344, 701 cm–1. HRMS
˜
(ESI): calcd. for C19H17FNO [M + H]+ 294.1289; found 294.1301.
4-Ethoxy-4ЈЈ-(trifluoromethyl)-1,1Ј:3Ј,1ЈЈ-terphenyl (9): Compound
9 was prepared according to the general procedure B by reacting 1c
(24 μL, 0.2 mmol) with potassium (4-ethoxyphenyl)trifluoroborate
(46 mg, 0.2 mmol), sodium carbonate (170 mg, 1.6 mmol), potas-
sium chloride (7 mg, 0.1 mmol), triphenylphosphine (3.0 mg,
6 mol-%), and tetrakis(triphenylphosphine)palladium(0) (7.0 mg,
3 mol-%) in a mixture of degassed toluene/ethanol (1.40:0.35 mL)
and degassed water (0.70 mL). The reaction mixture was stirred at
40 °C for 6 h. (4-Trifluoromethylphenyl)boronic acid (76 mg,
0.4 mmol) was then added, and the mixture was heated at 70 °C
for 20 h. After extraction, purification of the crude material by
flash column chromatography on silica gel (2% CH2Cl2 in heptane)
afforded 9 as a white powder (39 mg, 58%).
1
heptane) afforded 7db as a white powder (62 mg, 57%). H NMR
(75 MHz, CDCl3): δ = 0.85 (t, J = 7.2 Hz, 3 H), 1.27 (t, J = 7.2 Hz,
3 H), 2.31 (s, 3 H), 3.96 (q, J = 7.2 Hz, 2 H), 4.28 (q, J = 7.2 Hz,
2 H), 6.02 (s, 2 H), 6.95 (d, J = 6.9 Hz, 2 H), 7.06–7.28 (m, 7 H)
ppm. 13C NMR (75 MHz, CDCl3): δ = 13.5 (CH3), 14.0 (CH3),
21.3 (CH3), 49.6 (CH2), 61.3 (CH2), 61.8 (CH2), 118.0 (q, J =
318.0 Hz, CF3), 118.3 (C), 123.4 (C), 123.5 (C), 126.2 (2 CH), 126.7
(C), 127.4 (CH), 128.5 (2 CH), 128.6 (2 CH), 130.1 (2 CH), 136.0
(C), 137.7 (C), 137.8 (C), 159.1 (C), 160.6 (C) ppm. IR (neat): ν =
˜
2963, 1718, 1424, 1289, 1220, 1187, 1133, 1021, 925, 820, 697 cm–1.
HRMS (ESI): calcd. for C25H25F3NO7S [M + H]+ 540.1304; found
540.1299.
Compound 9 was also prepared according to the general procedure
B by reacting 6b (75 mg, 0.2 mmol) with potassium (4-ethoxy-
phenyl)trifluoroborate (46 mg, 0.2 mmol), sodium carbonate
(170 mg, 1.6 mmol), potassium chloride (7 mg, 0.1 mmol), tri-
phenylphosphine (3.0 mg, 6 mol-%), and tetrakis(triphenylphos-
phine)palladium(0) (7.0 mg, 3 mol-%) in a mixture of degassed tol-
uene/ethanol (1.40:0.35 mL) and degassed water (0.70 mL). The re-
action mixture was first stirred at 70 °C for 20 h. (4-Trifluoro-
methylphenyl)boronic acid (38 mg, 0.2 mmol) was then added, and
the mixture was heated at 70 °C or 20 h. After extraction, purifica-
tion of the crude material by preparative TLC (2% CH2Cl2 in hept-
ane) afforded 9 as a white powder (42 mg, 62%). 1H NMR
(300 MHz, CDCl3): δ = 1.43 (t, J = 7.0 Hz, 3 H), 4.08 (q, J =
7.0 Hz, 2 H), 6.98 (d, J = 8.7 Hz, 2 H), 7.47–7.61 (m, 5 H), 7.66–
7.79 (m, 5 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 15.1 (CH3),
63.8 (CH2), 115.1 (2 CH), 124.5 (q, J = 271.8 Hz, CF3), 125.8 (CH),
125.9 (q, J = 3.6 Hz, 2 CH), 126.0 (CH), 126.8 (CH), 127.7 (2 CH),
128.5 (2 CH), 129.6 (CH), 129.7 (q, J = 32.0 Hz, C), 133.4 (C),
Diethyl N-Benzyl-3-(4-nitrophenyl)-4-(trifluoromethylsulfonyloxy)-
pyrrole-2,5-dicarboxylate (7dc): Compound 7dc was prepared ac-
cording to general procedure A by reacting pyrrole 6d (60 mg,
0.1 mmol) with potassium (4-nitrophenyl)trifluoroborate (23 mg,
0.1 mmol), sodium carbonate (43 mg, 0.4 mmol), potassium chlor-
ide (7 mg, 0.1 mmol), triphenylphosphine (1.5 mg, 3 mol-%), and
tetrakis(triphenylphosphine)palladium(0) (3.5 mg, 1.5 mol-%) in a
mixture of degassed toluene/ethanol (0.70:0.20 mL) and degassed
water (0.35 mL). The reaction mixture was stirred at 70 °C over-
night. After extraction, purification of the crude material by flash
column chromatography on silica gel (10% EtOAc in heptane) af-
1
forded 7dc as a white powder (17 mg, 31%). H NMR (300 MHz,
CDCl3): δ = 0.85 (t, J = 7.2 Hz, 3 H), 1.28 (t, J = 7.2 Hz, 3 H),
3.98 (q, J = 7.2 Hz, 2 H), 4.30 (q, J = 7.2 Hz, 2 H), 6.08 (s, 2 H),
6.96 (d, J = 6.9 Hz, 2 H), 7.17–7.31 (m, 3 H), 7.44 (d, J = 8.7 Hz,
2 H), 8.19 (d, J = 8.7 Hz, 2 H) ppm. 13C NMR (75 MHz, CDCl3):
δ = 13.5 (CH3), 13.9 (CH3), 49.9 (CH2), 61.7 (CH2), 62.2 (CH2),
117.9 (q, J = 319.5 Hz, CF3), 119.1 (C), 121.2 (C), 123.0 (2 CH),
123.2 (C), 126.3 (2 CH), 127.6 (CH), 128.7 (2 CH), 131.4 (2 CH),
140.5 (C), 141.9 (C), 145.0 (C), 159.0 (C) ppm. IR (neat): ν = 2987,
˜
2926, 1605, 1516, 1475, 1328, 1252, 1170, 1129 cm–1. HRMS (ESI):
calcd. for C25H24F3N2O [M + 2MeCN + H]+ 425.1841; found
425.2329.
135.4 (C), 137.1 (C), 137.2 (C), 147.5 (C), 158.9 (C), 159.8 (C) ppm. Diethyl N-Benzyl-3-[2-benzyloxy)phenyl]-4-(3,4-dimethoxyphenyl)-
IR (neat): ν = 2919, 1726, 1524, 1421, 1348, 1276, 1216, 1187, 1133,
pyrrole-2,5-dicarboxylate (10): Compound 10 was prepared accord-
ing to general procedure B by reacting 6d (60 mg, 0.1 mmol)
with potassium (3,4-dimethoxyphenyl)trifluoroborate (25 mg,
˜
1018, 930, 853, 760 cm–1. HRMS (ESI): calcd. for C24H22F3N2O9S
[M + H]+ 571.0998; found 571.0973.
12
www.eurjoc.org
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O40090
/KAP1
Date: 26-03-14 17:30:37
Pages: 15
Selective Suzuki–Miyaura Monocouplings
2555–2561; c) 1,8-dibromonaphthalene tends to favor dicou-
0.1 mmol), sodium carbonate (85 mg, 0.8 mmol), potassium chlor-
ide (3.5 mg, 0.05 mmol), triphenylphosphine (1.5 mg, 6 mol-%),
and tetrakis(triphenylphosphine)palladium(0) (3.5 mg, 3 mol-%) in
a mixture of degassed toluene/ethanol (0.7:0.2 mL) and degassed
water (0.35 mL). The reaction mixture was first stirred at 70 °C
for 20 h. (2-Benzyloxyphenyl)boronic acid (27 mg, 0.12 mmol) was
then added at room temp., and the mixture was heated to 100 °C
for 20 h. After filtration through silica, chromatography of the
crude reaction product on silica with 0 to 20% EtOAc in heptane
pling over monocoupling, see: C. F. R. A. C. Lima, J. E. Rodri-
guez-Borges, L. M. N. B. F. Santos, Tetrahedron 2011, 67, 689–
697.
C.-G. Dong, T.-P. Liu, Q.-S. Hu, Synlett 2009, 1081–1086.
E. Ullah, J. McNulty, A. Robertson, Eur. J. Org. Chem. 2012,
2127–2131.
a) For tetrachloropyrimidine, see: M. Hussain, N. T. Hung,
R. A. Khera, I. Malik, D. S. Zinad, P. Langer, Adv. Synth. Ca-
tal. 2010, 352, 1429–1433; b) for pentachloropyridine, see: P.
Ehlers, S. Reimann, S. Erfle, A. Villinger, P. Langer, Synlett
2010, 1528–1532; c) for tetrabromothiophenes, see: D. T. Tùng,
D. T. Tun, N. Rasool, A. Villinger, H. Reinke, C. Fischer, P.
Langer, Adv. Synth. Catal. 2009, 351, 1595–1609; d) for tetra-
bromopyrroles, see: T. T. Dang, R. Ahmad, T. T. Dang, H.
Reinke, C. Fischer, P. Langer, Tetrahedron Lett. 2008, 49, 1698–
1700.
[7]
[8]
[9]
afforded 10 as
a
white powder (47.0 mg, 76%). 1H NMR
(300 MHz, CDCl3): δ = 0.68 (t, J = 6.8 Hz, 3 H), 0.83 (t, J =
6.8 Hz, 3 H), 3.43 (s, 3 H), 3.72 (s, 3 H), 3.86 (q, J = 6.8 Hz, 2 H),
3.94 (q, J = 6.8 Hz, 2 H), 4.84 (s, 2 H), 6.03 (s, 2 H), 6.50 (s, 1 H),
6.57 (s, 1 H), 6.58 (s, 1 H), 6.74 (d, J = 7.4 Hz, 2 H), 6.90 (dd, J =
7.4, 1.2 Hz, 1 H), 7.05–6.98 (m, 2 H), 7.28–7.06 (m, 9 H) ppm. 13
C
NMR (75 MHz, CDCl3): δ = 13.3 (CH3), 13.6 (CH3), 49.6 (CH2),
55.4 (CH3), 55.7 (CH3), 60.2 (CH2), 60.6 (CH2), 69.8 (CH2), 109.9
(CH), 111.9 (CH), 113.5 (CH), 120.3 (CH), 122.6 (CH), 124.8 (C),
124.9 (C), 125.2 (C), 126.2 (2 CH), 126.7 (2 CH), 126.8 (CH), 127.2
(C), 127.5 (CH), 127.8 (C), 128.2 (CH), 128.4 (2 CH), 128.5 (2
CH), 131.2 (C), 132.0 (CH), 137.4 (C), 139.1 (C), 147.4 (C), 147.5
[10]
[11]
[12]
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hedron Lett. 2003, 44, 4443–4446.
(C), 156.4 (C), 161.4 (C), 161.8 (C) ppm. IR (neat): ν = 2927, 2853,
˜
1712, 1454, 1234, 1200, 1138, 1027, 731 cm–1. HRMS (ESI): calcd.
for C38H38NO7 [M + H]+ 620.2643; found 620.2660.
Supporting Information (see footnote on the first page of this arti-
1
cle): Copies of H and 13C NMR spectra.
[13]
[14]
Acknowledgments
The authors wish to thank the Institut de Chimie des Substances
Naturelles for financial support and a fellowship (to C. M.) and
the Labex LERMIT for financial support and a fellowship (to C.
P.).
[15]
[16]
For detailed mechanistic studies on the Suzuki–Miyaura cross-
coupling, see: a) C. Amatore, A. Jutand, G. Le Duc, Chem.
Eur. J. 2012, 18, 6616–6625; b) C. Amatore, A. Jutand, G.
Le Duc, Angew. Chem. Int. Ed. 2012, 51, 1379–1382; Angew.
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J. F. Hartwig, J. Am. Chem. Soc. 2011, 133, 2116–2119; e) C.
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[1] a) A. de Meijere, F. Diederich (Eds.), Metal-Catalyzed Cross-
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M. Lemaire, Chem. Rev. 2002, 102, 1359–1470.
[2] For reviews and leading references, see: a) A. Suzuki, Angew.
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6854–6869; b) A. Suzuki, Y. Yamamoto, Chem. Lett. 2011, 40,
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yaura, K. Yamada, A. Suzuki, Tetrahedron Lett. 1979, 20,
3437–3440.
[3] a) For an overview of this topic, see: M. Tobisu, N. Chatani,
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2011, 121, 3617–3620; b) for a recent example concerning the
triple functionalization of phloroglucinol derivatives to yield
tetraaryls, see: F. Zhao, Y.-F. Zhang, J. Wen, D.-G. Yu, J.-B.
Wei, Z. Xi, Z.-J. Shi, Org. Lett. 2013, 15, 3230–3233.
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1427; e) S. Schröter, C. Stock, T. Bach, Tetrahedron 2005, 61,
2245–2267.
Indeed, recent studies have shown that the nature of the boron
derivative can have an important influence on the outcome of
the reaction, mainly by influencing the rate of release of the
active boronic acid, see: a) A. J. J. Lennox, G. C. Lloyd-Jones,
J. Am. Chem. Soc. 2012, 134, 7431–7441; b) N. Zhang, D. J.
Hoffman, N. Gutsche, J. Gupta, V. Percec, J. Org. Chem. 2012,
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These conditions were adapted from our previous work on one-
pot double Suzuki–Miyaura couplings (see ref.[11]), for which
we were able to lower the amount of catalyst and additive
(KCl) without hampering the efficiency of the reaction. More-
over, for a monocoupling, only 4 equiv. of base are necessary,
but, at this stage, we felt that it would be interesting to set
reaction conditions that would already be suitable for the one-
pot sequential double coupling reaction developed thereafter.
The positive role of alkali halides additives such as KCl in Su-
zuki–Miyaura cross-couplings has been reported and rational-
ized early on for reactions involving aryltriflates: a) T. Oh-e,
N. Miyaura, A. Suzuki, Synlett 1990, 221–223; b) T. Oh-e, N.
[17]
[5] Y. Uozumi, M. Kikuchi, Synlett 2005, 1775–1778.
[6] a) D. J. Sinclair, M. S. Sherburn, J. Org. Chem. 2005, 70, 3730–
3733; b) for monocoupling with an excess of the dibromo ar-
ene, see also: E. Guillén, J. Hierrezuelo, R. Martínez-Mallor-
quín, J. M. López-Romero, R. Rico, Tetrahedron 2011, 67,
Eur. J. Org. Chem. 0000, 0–0
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Pages: 15
C. Minard, C. Palacio, K. Cariou, R. H. Dodd
FULL PAPER
Miyaura, A. Suzuki, J. Org. Chem. 1993, 58, 2201–2208. Sim-
ilar positive effects have also been witnessed for aryl halides,
for a recent report on this subject, see: c) B. Zhang, J. Song,
H. Liu, J. Shi, J. Ma, H. Fan, W. Wang, P. Zhang, B. Han,
Green Chem. 2014, 16, 1198–1201.
[20] For seminal work on one-pot double Suzuki–Miyaura cou-
plings of unsymmetrical dihaloarenes, see: a) S. C. Anderson,
S. T. Handy, Synthesis 2010, 2721–2724; b) S. Varello, S. T.
Handy, Synthesis 2009, 138–142; c) S. T. Handy, T. Wilson, A.
Muth, J. Org. Chem. 2007, 72, 8496–8500. For a one-pot
double Suzuki–Miyaura coupling of differentiated diboron
compounds, see: d) G. A. Molander, D. L. Sandrock, J. Am.
Chem. Soc. 2008, 130, 15792–15793.
[21] The corresponding p-methoxyterphenyl has been prepared by
different procedures from noncommercial starting materials
and in both cases the yields are under 50%: a) M.-Y. Chang,
C.-K. Chan, S.-Y. Lin, M.-H. Wu, Tetrahedron 2013, 69, 9616–
9624; b) P. García-García, M. A. Fernández-Rodríguez, E. Ag-
uilar, Angew. Chem. Int. Ed. 2009, 48, 5534–5537; Angew.
Chem. 2009, 121, 5642–5645.
[18] It has also been proposed that the Pd/phosphine ratio as well as
the nature of the phosphine might also influence the diffusion
process of the active catalyst and that increasing the diffusion
would allow the active catalyst to “escape” the vicinity of the
monocoupled adduct and, thus, favor the selectivity of the pro-
cess, see ref.[7] and: C.-G. Dong, Q.-S. Hu, J. Am. Chem. Soc.
2005, 127, 10006–10007.
[19] For reviews on potassium trifluoroborates, see: a) S. Darses, J.-
P. Genêt, Chem. Rev. 2008, 108, 288–325; b) G. A. Molander,
N. Ellis, Acc. Chem. Res. 2007, 40, 275–286. A notable advan-
tage of using potassium trifluoroborates instead of boronic ac-
ids is that they help minimize and/or suppress unwanted side
reactions such as protodeboronation and oxidative homocou-
pling; for more details see ref.[16c,16d]
[22] T. Ishiyama, M. Murata, N. Miyaura, J. Org. Chem. 1995, 60,
7508–7510.
Received: January 19, 2014
Published Online: ᭿
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Job/Unit: O40090
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Date: 26-03-14 17:30:37
Pages: 15
Selective Suzuki–Miyaura Monocouplings
Cross-Coupling
C. Minard, C. Palacio, K. Cariou,
R. H. Dodd* ................................... 1–15
Selective Suzuki–Miyaura Monocouplings
with Symmetrical Dibromoarenes and Aryl
Ditriflates for the One-Pot Synthesis of
Unsymmetrical Triaryls
Keywords: Synthetic methods / C–C cou-
pling / Cross-coupling / Palladium
By studying several key parameters, the
factors that allow selective Suzuki–Mi-
yaura monocoupling of symmetrical di-
haloarenes have been outlined. This study
serves as the basis for the efficient synthesis
of unsymmetrical triaryls from symmetrical
dibromoarenes and aryl ditriflates by a
one-pot desymmetrizing double Suzuki–
Miyaura coupling.
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
15