Suzuki-Miyaura coupling of aryl iodides, bromides, and chlorides catalyzed by bis(thiazole) pincer palladium complexes

Article abstract of DOI:10.1021/jo3011733

Bis(thiazole) pincer palladium complexes showed efficient catalytic activity for the Suzuki-Miyaura coupling of aryl halides, allowing the synthesis of biaryls with very high turnover numbers and turnover frequencies. The complexes were successfully applied in the scalable and green synthesis of the key intermediates of bioactive LUF5771 and its analogues.

Full text of DOI:10.1021/jo3011733

Note
pubs.acs.org/joc
Suzuki−Miyaura Coupling of Aryl Iodides, Bromides, and Chlorides
Catalyzed by Bis(thiazole) Pincer Palladium Complexes
Qun-Li Luo,* Jian-Ping Tan, Zhi-Fu Li, Wen-Hui Nan, and Dong-Rong Xiao*
College of Chemistry and Chemical Engineering, Southwest University, Chongqing, 400715, China
S
* Supporting Information
ABSTRACT: Bis(thiazole) pincer palladium complexes showed
efficient catalytic activity for the Suzuki−Miyaura coupling of aryl
halides, allowing the synthesis of biaryls with very high turnover
numbers and turnover frequencies. The complexes were
successfully applied in the scalable and green synthesis of the
key intermediates of bioactive LUF5771 and its analogues.
alladium-catalyzed cross-coupling reactions are versatile
tools in modern organic synthesis.1 Among these trans-
ing our interest in the development of bis(azoline) pincer
complexes and their applications,20−22 we herein report the
synthesis, characterization, and catalysis study of symmetrical
NCN pincer-Pd complexes containing bis(thiazole) motifs in
the SM coupling of aryl halides (Figure 1, complexes 1 and 2).
P
formations, Suzuki−Miyaura (SM) coupling undoubtedly
belongs to the most powerful methods for C−C bond
construction.2,3 Palladacycles, a class of organopalladium
derivatives containing at least one Pd−C bond, are able to
efficiently catalyze SM coupling.4,5 Pincer palladium complexes
are well-defined palladacycles that contain a Pd−C bond
stabilized by the intramolecular coordination of two neutral
donor atoms (N, P, As, O, Se, or S).6−8 The rich chemistry of
pincer-Pd complexes has attracted considerable attention,9−12
and a plethora of pincer-Pd compounds were available for
catalyzing the SM coupling.13 The catalytic activities of these
complexes depended on the structure of their ligands. The
most efficient pincer-Pd complexes were those containing
phosphines or phosphine mimics (such as N-heterocyclic
carbenes, NHCs) as ligands.14,15 The NCN type of pincer-Pd
complexes, containing two nitrogen atoms as donating sites in
the coordination sphere, were developed as a variety of
nonphosphine pincer catalytic system.6 To date, most NCN
pincer-Pd systems were only able to catalyze the couplings of
relatively active substrates,4 and those lacking phosphorus and
NHCs in their ligands were rarely active toward the coupling of
the less active substrates, such as ortho-disubstituted bromo-
benzenes and chloroarenes. There were no symmetrical
examples and only one unsymmetrical example of NCN
palladium complexes that allowed the use of aryl chlorides in
SM coupling.16
Figure 1. Bis(azoline) pincer complexes 1−4.
These complexes were robust for catalyzing the SM coupling of
less active aryl halides, such as bromophenols, ortho-
disubstituted bromobenzenes, and chloroarenes.
The synthetic routes of complexes 1 and 2 are summarized in
the Supporting Information (Scheme S1). The solid state
structures were determined by single-crystal X-ray diffraction.23
The synthesis of complexes 3 and 4 was reported previously.21
The catalytic investigation began with an examination of the
coupling of 4-methoxybromobenzene with PhB(OH)2 to
evaluate the catalytic activities of complexes 1−4 (Table 1,
Entries 1−4). The results showed that the activity of the
complexes was 1 > 2 > 3 > 4. Complexes 1 and 2, containing
the same bis(thiazole) pincer structure, were of similar activity
and greatly superior to complexes 3 and 4, which indicated that
the pincer scaffold of the Pd complexes [bis(thiazole) vs
bis(oxazole) and thiazole-oxazole in complexes 1, 3, and 4,
respectively] had more impact on the catalytic activity than the
ligand ion (bromine ion vs acetate ion in complexes 1 and 2,
respectively). Because the pincer scaffold in complexes 1 and 2
is same and their catalytic activities were close, the activity test
was hereafter focused on complex 1. In the SM coupling
performed with bromoarenes (Table 1, Entries 5−17), the
As five-membered heterocyclic structures, thiazoles can be
used as N-donor ligands. However, thiazole-derived tridentate
ligands are underrepresented in the chemistry of coordination
compounds.17,18 Recently, Odinets and co-workers reported
that an unsymmetrical SCN pincer complex, bearing a
thiophosphoryl and a benzothiazole ring as donating sites,
showed an ability to efficiently promote the SM coupling of
chloroacetophenone.19 Symmetrical pincer structures have
many advantages over unsymmetrical ones, such as structural
simplicity and synthetic conciseness and convenience. Follow-
Received: June 8, 2012
Published: August 28, 2012
© 2012 American Chemical Society
8332
dx.doi.org/10.1021/jo3011733 | J. Org. Chem. 2012, 77, 8332−8337

The Journal of Organic Chemistry
Note
2-bromotoluene and 2,6-dimethylbromobenzene) (Table 2,
Entries 14−16). The catalytic efficiency of complex 1 toward
bromoarenes was close to that of the phosphorus-containing
complex 8 {C6H3[NHP(piperidinyl)2]2Pd(Cl)},28 and better
than that of many NHC-type pincer-Pd complexes.15,29
Notably, the reactions gave good results for activated aryl
chlorides (Table 2, Entries 18−24), and TON was up to 4400
(Table 2, Entry 20), the same order of magnitude as PCP
pincer complex 830 for chloroarenes. Unactivated chloroarenes
also worked using complex 1, but with lower yields (Table 2,
Entries 25 and 26). According to the literature,16,19,30−35 the
best results for coupling of aryl chlorides were achieved with
phosphorus-containing pincer complexes or with palladacycles
modified by carbenes. The pincer-Pd complexes that contained
phosphorus-free ligands and were active toward aryl chlorides
were extremely rare. A comparison of catalytic efficiency among
the most active pincer-Pd complexes known to catalyze the SM
coupling of chloroarenes with arylboronic acids is discussed in
the Supporting Information. Complex 1 was the first example
of a symmetrical NCN pincer-Pd complex that completely
lacked phosphorus and NHCs in its ligand while allowing the
use of chloroarenes in SM coupling. Overall, complex 1 ranks
among the most active pincer complexes suggested for this
reaction.
The catalytic efficiency of complex 1 was further exemplified
in the synthesis of terphenyl-derived antagonists of the
luteinizing hormone (LH) receptor (Scheme 1). The
terphenylcarbamate derivatives 10, especially LUF5771 (10a),
were recently identified as efficient LH-receptor antagonists by
Heitman and co-workers.36 However, because of the relatively
low activity of bromophenol (5n), the key intermediates 9 were
prepared in poor to moderate yields (34−71%) via SM
couplings catalyzed by the classic Pd reagent Pd(PPh3)4. A
good alternative for the preparation of 9, newly reported by
Stahl and co-workers, was to transform the substituted
cyclohexanones into the targeted diarylphenol derivatives via
palladium-catalyzed oxidative dehydrogenation (Scheme 1,
reaction (iii)).37 Nevertheless, the SM coupling-involved
route is believed to be more concise. Subsequently, the
catalytic behavior of complex 1 was examined in the synthesis
of disubstituted phenols 9a and 9b. As shown in Scheme 1, the
catalytic efficiency of complex 1 was distinguished by its
practicality, and this protocol integrated several advantages
compared with the results above. (1) The catalyst loading was
as low as 0.1 mol % [Pd] or less (Scheme 1, Entries 1−6),
much lower than those required above. (2) The couplings
catalyzed by complex 1 underwent a greener reaction condition,
in which no organic solvent or other additives were required
except the catalyst, common inorganic base, and water. (3) This
protocol permitted the operations to be managed in a very
convenient way. The reactions did not need susceptible
reagents or special equipment. Complex 1 is stable toward air
and moisture, and the couplings could be carried out under
aerobic conditions. Thus, the reaction installation did not
require strictly air-free techniques. (4) The scale up (from
milligram-scale to gram-scale) of the reaction hardly affected
the catalytic efficiency. Comparatively, Stahl’s method was also
capable of scale-up, but it needed a prolonged reaction time of
48 h and an extra portion of catalyst.
Table 1. Catalyst Screening and Reaction Condition
Optimization for the SM Coupling Performed with 4-
Methoxybromobenzene
a
[Pd]
time
(h)
isolated
entry
1
(loading)
solvent
dioxane
base
K2CO3
yield (%)
1 (0.05
mol %)
15
15
15
15
97
94
52
18
2
3
4
2 (0.05
mol %)
dioxane
dioxane
dioxane
K2CO3
K2CO3
K2CO3
3 (0.05
mol %)
4 (0.05
mol %)
5
1 (1 mol %) dioxane
1 (1 mol %) DMSO
1 (1 mol %) DMF
1 (1 mol %) toluene
1 (1 mol %) p-xylene
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
4
4
4
4
4
4
99
5
6
7
63
83
97
trace
8
9
10
1 (1 mol %) tBuOH/H2O
(9:1)
11
12
13
14
15
16
17
1 (1 mol %) dioxane
1 (1 mol %) dioxane
1 (1 mol %) dioxane
1 (1 mol %) dioxane
1 (1 mol %) dioxane
1 (1 mol %) dioxane
1 (1 mol %) dioxane
K3PO4·3H2O
NaOH
KOAc
4
4
4
4
4
4
4
95
44
19
17
85
4
KF
Cs2CO3
NEt3
pyridine
trace
a
Reaction conditions: 5a (1 mmol), 6a (1.5 mmol), pincer-Pd
complex (indicated amount), base (3 mmol) and solvent (5 mL). The
product was isolated by chromatographic purification on silica column.
change of solvent or base strongly influenced the isolated yields.
The best results were obtained with 1,4-dioxane as solvent
(Entry 5 vs Entries 6−10) and K2CO3 as base (Entry 5 vs
Entries 11−17), whereas neither polar solvents (Entries 6 and
10) nor organic bases (Entries 16 and 17) yielded good results.
With the optimized reaction conditions, we further examined
the catalytic activity of complex 1 in the SM coupling of various
haloarenes with organoboronic acids. As shown in Table 2,
complex 1 was a robust (pre)catalyst toward SM coupling.
Iodoarenes (Table 2, Entries 1−7) underwent coupling with a
turnover number (TON) of up to 1.9 × 108 and a turnover
frequency (TOF) of up to 5 × 106 h−1 (Table 2, Entry 5). The
catalytic efficiency is better than that of the NHC-type pincer-
Pd complexes.24−26 Remarkably, the couplings could afford the
desired product in fair yield even with a ppm scale catalyst
loading (Table 2, Entries 2−5, with 2 × 10−6 mol % Pd-loading,
61% of yield). Palladium-catalyzed reactions frequently present
the problem that the products were contaminated by a high
level of residual palladium (typically 300−2000 ppm). With a
palladium loading as low as 2 × 10−6 mol %, the problem of Pd
residue could be ignored if the coupling yield exceeded 40%
because the total amount of palladium from the (pre)catalyst
did not exceed the level of residual palladium in the active
pharmaceutical ingredients required by government regulations
(typically <5 ppm).27 The coupling of iodoarenes worked well
at a temperature of less than 90 °C (Table 2, Entries 1 and 6).
For deactivated bromoarenes, excellent yields were obtained
under aerobic conditions with 0.01−0.05 mol % of complex 1
(Table 2, Entries 8−17). Complex 1 also showed potent
catalytic activities toward the sterically hindered substrates (e.g.,
In conclusion, two bis(thiazole) NCN-type pincer palladium-
(II) complexes were synthesized through a facile route in good
yields. Their solid structures were confirmed by single-crystal
X-ray diffraction. Complex 1 was proved to be highly robust
8333
dx.doi.org/10.1021/jo3011733 | J. Org. Chem. 2012, 77, 8332−8337

The Journal of Organic Chemistry
Note
a
Table 2. Evaluation of the Catalytic Activity of Complex 1 in the SM Coupling of Aryl Halide
b
entry
5
X
6
7
[Pd] (loading)
T (°C)
t (h)
yield
TON
980
TOF (h−1
)
1
5b
5b
5b
5b
5b
5b
5c
5a
5a
5a
5d
5d
5e
5f
I
6a
6a
6a
6a
6a
6b
6a
6a
6a
6a
6a
6c
6a
6a
6a
6a
6a
6a
6a
6a
6c
6d
6a
6a
6a
6a
7a
7a
7a
7a
7a
7b
7c
7a
7a
7a
7b
7d
7e
7f
1 (0.1 mol %)
90
28
20
30
38
38
8
98
96
88
61
38
92
99
97
75
22
95
98
97
83
70
98
98
89
76
44
61
80
85
74
21
21
35
2
I
1 (2 × 10−4 mol %)
1 (2 × 10−5 mol %)
1 (2 × 10−6 mol %)
1 (2 × 10−7 mol %)
1 (1 × 10−3 mol %)
1 (1 × 10−4 mol %)
1 (0.05 mol %)
1 (5 × 10−3 mol %)
1 (5 × 10−4 mol %)
1 (0.05 mol %)
1 (0.5 mol %)
110
115
115
115
80
4.8 × 105
4.4 × 106
3.0 × 107
1.9 × 108
9.2 × 104
9.9 × 105
1.9 × 103
1.5 × 104
5.5 × 104
1.9 × 103
196
1.9 × 103
1.6 × 103
1.4 × 103
980
9.8 × 103
89
2.4 × 104
1.5 × 105
8.0 × 105
5.0 × 106
1.1 × 104
4.9 × 104
129
3
I
4
I
5
I
6
I
7
I
110
110
110
110
110
110
110
110
110
110
110
110
110
110
110
110
110
110
110
110
20
15
36
48
12
6
8
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
9
416
10
11
12
13
14
15
16
17
18
1.1 × 103
158
32
1 (0.05 mol %)
1 (0.05 mol %)
1 (0.05 mol %)
1 (0.1 mol %)
24
24
24
24
18
24
24
24
24
24
24
24
40
24
81
69
5g
5g
5h
5i
7g
7g
7h
7i
58
41
1 (0.01 mol %)
1 (1 mol %)
544
3.7
c
19
5i
7i
1 (0.1 mol %)
760
31.7
c
20
5i
7i
1 (0.01 mol %)
1 (1 mol %)
4.4 × 103
61
183
d
21
5i
7j
2.5
d
22
5i
7k
7l
1 (1 mol %)
80
3.3
e
23
f
5j
1 (0.5 mol %)
170
7.1
24
5k
5l
7m
7n
7a
1 (1 mol %)
74
3.1
c
25
1 (1 mol %)
21
0.5
d
26
5m
1 (1 mol %)
21
0.9
a
Reaction conditions: 5 (1 mmol), 6 (1.5 mmol), 1 (indicated amount), K2CO3 (3 mmol), and 1,4-dioxane (5 mL), for entries 1−17, under the
ambient atmosphere; for entries 18−26, under argon atmosphere. TON: turnover number, ratio of yield to catalyst amount. TOF: turn over
frequency, ratio of TON to reaction time. Isolated yields are given in all cases. Added NaBr (1 equiv). Added H3BO3 (50 mol %). Added TBAB
(1 equiv). Added PPh3 (3 mol %).
b
c
d
e
f
Scheme 1. Applications of 1 in the Catalytic Synthesis of Terphenyl-Derived Antagonists of the Luteinizing Hormone Receptor
a
Reaction scales are based on 5n.
(pre)catalyst for the SM couplings of less active aryl halides,
such as bromophenols, ortho-disubstituted bromobenzenes, and
chloroarenes. This was the first example of symmetrical NCN
pincer-Pd complexes that lacked phosphorus and N-hetero-
cyclic carbene in the ligands while being capable of catalyzing
the Suzuki−Miyaura cross-coupling of chloroarenes. The
8334
dx.doi.org/10.1021/jo3011733 | J. Org. Chem. 2012, 77, 8332−8337

The Journal of Organic Chemistry
Note
indicated amount of complex 1. If the amount of 1 was less than 1.0
mg, an appropriate volume of a solution of 1 was used (the solution at
an initial concentration of 0.04 mol·L−1 in NMP was progressively
diluted with dioxane), and the total volume of the solvents was 5.0 mL
in each reaction. For the reactions in which inert atmosphere was not
required, the outlet of the condenser was connected to a paraffin-filled
bubble counter, while for those required, standard Schlenk-line
techniques were applied under argon atmosphere. The mixture was
heated at an indicated temperature (typically, at 110 °C) and
continually stirred until the consumption of aryl halide (monitoring
with TLC). After being cooled to the ambient temperature, it was
diluted with 10 mL of deionized water, and extracted with EtOAc
(three portions of 15 mL each). The combined organic phase was
washed with deionized water and saturated aqueous NaCl, dried over
anhydrous MgSO4, and then filtered and concentrated. The crude
product was purified by column chromatography (silica, hexane or
hexane/EtOAc mixture as eluent). The isolated coupling products
applications of 1 in the scalable and green synthesis of the key
intermediates of bioactive LUF5771 and its analogues highlight
the prospective utility in the synthesis of aryl-substituted arenes,
and could have a positive impact on laboratory- and industrial-
scale chemical synthesis.
EXPERIMENTAL SECTION
■
Synthesis of Complexes 1 and 2 (Scheme S1). 1-Bromo-2,6-
bis(2-methylthiazol-4-yl)benzene. 1-Bromo-2,6-bis(2-bromoacetyl)-
benzene38 (400 mg, 1 mmol) and thiacetamide (300 mg, 4 mmol)
were dissolved in 5 mL of DMF. After being stirred for 24 h at room
temperature, the resultant mixture was diluted with 15 mL of H2O,
and then extracted with EtOAc (three portions of 20 mL each). The
combined organic phase was successively washed with water and brine,
dried over anhydrous MgSO4, and then purified by column
chromatography (silica, hexanes/EtOAc 4:1 as eluent) to afford 1-
bromo-2,6-bis(2-methylthiazol-4-yl)benzene (296 mg, 84% yield) as
a pale yellow solid, mp 80 °C. 1H NMR (300 MHz, CDCl3): δ 7.61 (d,
3J = 7.5 Hz, 2H), 7.43 (s, 2H), 7.40 (t, 3J = 7.5 Hz, 1H), 2.79 (s, 6H).
1
were confirmed by H and 13C NMR.
4-Methoxybiphenyl (7a).40−42 1H NMR (300 MHz, CDCl3): δ
7.62−7.54 (m, 4H), 7.49−7.42 (m, 2H), 7.34 (tt, J = 1.6, 7.3 Hz, 1H),
7.02 (dt, J = 2.4, 8.7 Hz, 2H), 3.88 (s, 3H). 13C NMR (75 MHz,
CDCl3): δ 159.1, 140.7, 133.7, 128.7, 128.1, 126.7, 126.6, 114.1, 55.3.
(E)-4-Methoxystilbene (7b).43 1H NMR (300 MHz, CDCl3): δ
7.54−7.42 (m, 4H), 7.35 (t, J = 8.1 Hz, 2H), 7.24 (t, J = 6.8 Hz, 1H),
7.07 (d, J = 16.3 Hz, 1H), 6.99 (d, J = 16.5 Hz, 1H), 6.91 (d, J = 8.0
Hz, 2H), 3.84 (s, 3H). 13C NMR (75 MHz, CDCl3): δ 159.2, 137.6,
130.1, 128.6, 128.2, 127.7, 127.2, 126.6, 126.2, 114.1, 55.3.
4-Methylbiphenyl (7c).40−42 1H NMR (300 MHz, CDCl3): δ
7.62−7.57 (m, 2H), 7.51 (d, J = 8.1 Hz, 2H), 7.47−7.40 (m, 2H),
7.37−7.31 (m, 1H), 7.29−7.25 (m, 2H), 2.41 (s, 3H). 13C NMR (75
MHz, CDCl3): δ 141.2, 138.4, 137.0, 129.5, 128.7, 126.98, 126.96,
126.95, 21.1.
13C NMR (75 MHz, CDCl3): δ 164.6, 153.8, 137.3, 131.3, 127.1,
122.4, 117.4, 19.2. LRMS (ESI): m/z (%) 351 (95) (M++H), 353
(100) (M++2+H), 373 (22) (M++Na). Elemental analysis calcd (%)
for C14H11BrN2S2: C, 47.87; H, 3.16; N, 7.97; found: C, 47.96; H,
3.18; N, 8.20.
[Bromo-2,6-bis(2-methylthiazol-4-yl)phenylpalladium(II)] (1).
Under an argon atmosphere, a 25 mL Schlenk flask was charged
with 1-bromo-2,6-bis(2-methylthiazol-4-yl)benzene (106 mg, 0.3
39
mmol), Pd(dba)2 (173 mg, 0.3 mmol), and dry benzene (15 mL).
The reaction mixture was heated to reflux for 2 h, then cooled to room
temperature and stirred for further 2 h. The resultant mixture was
directly transferred on to a diatomite column and eluted first with
hexane to remove dibenzylideneacetone (dba) and then with mixed
solvent (CHCl3/MeOH = 3:1). The collected target compound 1 was
crystallized from CHCl3/MeOH as a slight yellow amorphous solid.
Yield 86%, mp >260 °C (decomp.). 1H NMR (300 MHz,
4-(4-Chlorophenyl)toluene (7d).44 1H NMR (300 MHz, CDCl3): δ
7.47 (d, J = 8.5 Hz, 2H), 7.43 (d, J = 8.0 Hz, 2H), 7.36 (d, J = 8.5 Hz,
2H), 7.23 (d, J = 7.9 Hz, 2H), 2.38 (s, 3H). 13C NMR (75 MHz,
CDCl3): δ 139.5, 137.4, 137.0, 133.0, 129.6, 128.8, 128.1, 126.8, 21.1.
Biphenyl (7e).40−42 1H NMR (300 MHz, CDCl3): δ 7.60 (d, J = 7.4
Hz, 4H), 7.44 (t, J = 7.4 Hz, 4H), 7.32 (t, J = 7.3 Hz, 2H). 13C NMR
(75 MHz, CDCl3): δ 141.2, 128.7, 127.2, 127.1.
3
3
[D6]DMSO): δ 7.96 (s, 2H), 7.43 (d, J = 7.5 Hz, 2H), 7.20 (d, J
= 7.5 Hz, 1H), 3.15 (s, 6H). 13C NMR (75 MHz, [D6]DMSO): δ
174.7, 159.8, 154.6, 136.9, 125.8, 121.2, 111.0, 21.0. LRMS (ESI): m/z
(%) 377 (64) (M+−Br), 418 (46) (M+−Br+CH3CN), 801 (100)
(2M++HCO2−2Br), 835 (22) (2M+−Br). HRMS (ESI) calcd for
C14H11N2S2Pd (M+−Br): 376.9397; found: 376.9389. HRMS (ESI)
calcd for C28H22BrN4S4Pd2 (2M+−Br): 832.7976; found: 832.7953.
Elemental analysis calcd (%) for C14H11BrN2S2Pd·0.5H2O: C, 36.03;
H, 2.59; N, 6.00; found: C, 36.02, H, 2.77; N, 5.88. The single crystals
of 1 suitable for X-ray diffraction analysis were grown by slow diffusion
of dichloromethane into its DMF solution.
2-Methylbiphenyl (7f).41 1H NMR (300 MHz, CDCl3): δ 7.43−
7.35 (m, 2H), 7.35−7.28 (m, 3H), 7.28−7.20 (m, 4H), 2.26 (s, 3H).
13C NMR (75 MHz, CDCl3): δ 141.9 (C × 2), 135.3, 130.3, 129.8,
129.2, 128.0, 127.2, 126.7, 125.7, 20.5.
2,6-Dimethylbiphenyl (7g).45 1H NMR (300 MHz, CDCl3): δ
7.47−7.40 (m, 2H), 7.38−7.31 (m, 1H), 7.21−7.09 (m, 5H), 2.04 (s,
6H). 13C NMR (75 MHz, CDCl3): δ 141.9, 141.1, 136.1, 129.0, 128.4,
127.3, 127.0, 126.6, 20.9.
[2,6-Bis(2-methylthiazol-4-yl)phenylpalladium(II) acetate] (2). A
25 mL flask was charged with AgOAc (86 mg, 0.51 mmol), 1 (80 mg,
0.17 mmol), and THF-H2O (V:V = 60:1, 12 mL). The reaction
mixture was stirred in the dark overnight, whereupon TLC analysis
showed that bromide had been consumed, and then filtered through
diatomite. The filter cake was washed with acetone three times and
dried in vacuo to afford 57 mg of 2 as an off-white amorphous solid.
Yield 76%, mp >160 °C (decomp.). 1H NMR (300 MHz,
4-Chlorobiphenyl (7h).40−42 1H NMR (300 MHz, CDCl3): δ 7.56
(d, J = 8.3 Hz, 2H), 7.53 (d, J = 9.9 Hz, 2H), 7.46−7.34 (m, 5H). 13C
NMR (75 MHz, CDCl3): δ 140.0, 139.6, 133.3, 128.88, 128.86, 128.4,
127.6, 127.0.
4-Nitrobiphenyl (7i).40−42 1H NMR (300 MHz, CDCl3): δ 8.30 (d,
J = 8.7 Hz, 2H), 7.74 (d, J = 8.7 Hz, 2H), 7.65−7.60 (m, 2H), 7.54−
7.41 (m, 3H). 13C NMR (75 MHz, CDCl3): δ 147.6, 147.0, 138.7,
129.1, 128.9, 127.8, 127.3, 124.1.
3
3
[D6]DMSO): δ 7.94 (s, 2H), 7.39 (d, J = 7.2 Hz, 2H), 7.15 (d, J
= 7.3 Hz, 1H), 2.79 (s, 6H), 1.84 (s, 3H). The 13C NMR of 2 was
unsuccessful due to the complex’s low solubility in the common
solvent. LRMS (ESI): m/z (%) 377 (57) (M+−OAc), 418 (28) (M+−
OAc+CH3CN), 801 (100) (2M+−2OAc+HCO2). HRMS (ESI) calcd
for C14H11N2S2Pd (M+−OAc): 376.9397; found: 376.9383. HRMS
(ESI) calcd for C28H22BrN4S4Pd2 (2M+−OAc): 812.8926; found:
812.8940. Crystals of 2 suitable for X-ray diffraction analysis were
grown by slow diffusion of EtOAc and hexane into a DMF-HOAc
solution of 1.
4-(4-Nitrophenyl)chlorobenzene (7j).40 1H NMR (300 MHz,
CDCl3): δ 8.28 (d, J = 8.8 Hz, 2H), 7.69 (d, J = 8.8 Hz, 2H), 7.55
(d, J = 8.6 Hz, 2H), 7.46 (d, J = 8.6 Hz, 2H). 13C NMR (75 MHz,
CDCl3): δ 147.1, 146.2, 137.1, 135.2, 129.3, 128.6, 127.6, 124.1.
4-(4-Nitrophenyl)toluene (7k).40 1H NMR (300 MHz, CDCl3): δ
8.28 (d, J = 8.8 Hz, 2H), 7.72 (d, J = 8.8 Hz, 2H), 7.53 (d, J = 8.1 Hz,
2H), 7.31 (d, J = 8.0 Hz, 2H), 2.43 (s, 3H). 13C NMR (75 MHz,
CDCl3): δ 147.5, 146.8, 139.1, 135.8, 129.9, 127.4, 127.2, 124.1, 21.2.
4-Phenylbenzonitrile (7l).41,42 1H NMR (300 MHz, CDCl3): δ
7.76−7.66 (m, 4H), 7.62−7.57 (m, 2H), 7.52−7.39 (m, 3H). 13C
NMR (75 MHz, CDCl3): δ 145.6, 139.1, 132.5, 129.1, 128.6, 127.7,
127.2, 118.9, 110.8.
General Procedure for the Suzuki−Miyaura Couplings
(Tables 1 and 2). A 10 mL reaction tube equipped with a condenser
was charged with a mixture of organoboronic acid (1.5 mmol), aryl
halide (1.0 mmol), anhydrous K2CO3 (3.0 mmol), an indicated
amount of additive (if necessary), 1,4-dioxane (5.0 mL), and an
4-Acetylbiphenyl (7m).40−42 1H NMR (300 MHz, CDCl3): δ 8.04
(d, J = 8.4 Hz, 2H), 7.68 (d, J = 8.4 Hz, 2H), 7.63 (d, J = 7.7 Hz, 2H),
8335
dx.doi.org/10.1021/jo3011733 | J. Org. Chem. 2012, 77, 8332−8337

The Journal of Organic Chemistry
Note
7.51−7.37 (m, 3H), 2.64 (s, 3H). 13C NMR (75 MHz, CDCl3): δ
197.7, 145.6, 139.7, 135.6, 128.85, 128.81, 128.1, 127.13, 127.08, 26.6.
p-Terphenyl (7n).42 1H NMR (300 MHz, CDCl3): δ 7.69 (s, 4H),
7.66 (d, J = 8.2 Hz, 4H), 7.47 (t, J = 7.3 Hz, 4H), 7.37 (t, J = 7.0 Hz,
2H). 13C NMR (75 MHz, CDCl3): δ 140.7, 140.1, 128.8, 127.5, 127.3,
127.0.
The authors thank the financial support from NSFC
(20971105) and the Fundamental Research Funds for the
Central Universities (XDJK2012B011).
REFERENCES
■
Synthetic Procedures of 3,5-Diphenylphenol (9a) and 3,5-
Ditolylphenol (9b) (Scheme 1). Miligram-Scale Synthesis. A 15
mL reaction flask equipped with a condenser was charged with a
mixture of phenylboronic acid (1.5 mmol), 3,5-dibromophenol (0.5
mmol), anhydrous K2CO3 (3.0 mmol), deionized water (3.0 mL), and
0.5 mL of the solution of 1 (5 × 10−4 mmol) in dioxane (the catalyst
solution at an initial concentration of 0.04 mol·L−1 in NMP was
progressively diluted into 1 × 10−3 mol·L−1 with dioxane). The outlet
of the condenser was connected to a paraffin-filled bubble counter.
The mixture was heated at 115 °C, and continually stirred until the
consumption of aryl halide (monitoring with TLC). After being cooled
to the ambient temperature, it was diluted with water (5 mL),
neutralized with 1 mol·L−1 HCl, and extracted with EtOAc (three
portions of 15 mL each). The combined organic phase was washed
with distilled water and saturated aqueous NaCl, dried over anhydrous
MgSO4, and then filtered and concentrated. The crude product was
purified by column chromatography (silica, hexane/EtOAc mixture as
(1) Handbook of Organopalladium Chemistry for Organic Synthesis,
Negishi, E., de Meijere, A., Eds.; Wiley-Interscience: New York, 2002.
(2) Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457−2483.
(3) Partyka, D. V. Chem. Rev. 2011, 111, 1529−1595.
(4) Beletskaya, I. P.; Cheprakov, A. V. J. Organomet. Chem. 2004, 689,
4055−4082.
(5) Peris, E.; Crabtree, R. H. Coord. Chem. Rev. 2004, 248, 2239−
2246.
(6) The chemistry of pincer compounds, Morales-Morales, D., Jensen,
C. M., Eds.; Elsevier: Amsterdam, 2007.
(7) Moreno, I.; SanMartin, R.; Ines, B.; Churruca, F.; Domínguez, E.
́
Inorg. Chim. Acta 2010, 363, 1903−1911.
(8) van Koten, G.; Gebbink., R. J. M. K. Dalton Trans. 2011, 40,
8731−8732.
(9) Dupont, J.; Consorti, C. S.; Spencer, J. Chem. Rev. 2005, 105,
2527−2571.
1
́
(10) Selander, N.; Szabo, K. J. Chem. Rev. 2011, 111, 2048−2076.
eluent). The isolated coupling products were confirmed by H NMR
and 13C NMR. For 3,5-diphenylphenol (9a),36,37 baby pink solid,
(11) Blacque, O.; Frech, C. M. Chem.Eur. J. 2010, 16, 1521−1531.
(12) Gerber, R.; Blacque, O.; Frech, C. M. Dalton Trans. 2011, 40,
8996−9003.
yield, 98%; 1H NMR (300 MHz, CDCl3): δ 7.63 (d, 3J = 7.2 Hz, 4H),
3
4
7.46 (t, J = 7.3 Hz, 4H), 7.41−7.35 (m, 3H), 7.06 (d, J = 1.4 Hz,
2H), 5.17 (s, 1H). 13C NMR (75 MHz, CDCl3): δ 156.1, 143.4, 140.7,
128.8, 127.6, 127.2, 118.9, 113.0. LRMS (ESI): m/z (%) = 115 (100)
(2CH3CN+MeOH+H+), 247 (67) (M++H), 288 (36) (M++CH3CN
(13) Niu, J.-L.; Hao, X.-Q.; Gong, J.-F.; Song, M.-P. Dalton Trans.
2011, 40, 5135−5150.
(14) Marion, N.; Navarro, O.; Mei, J.; Stevens, E. D.; Scott, N. M.;
Nolan, S. P. J. Am. Chem. Soc. 2006, 128, 4101−4111.
(15) Godoy, F.; Segarra, C.; Poyatos, M.; Peris, E. Organometallics
2011, 30, 684−688.
(16) Hao, X.-Q.; Wang, Y.-N.; Liu, J.-R.; Wang, K.-L.; Gong, J.-F.;
Song, M.-P. J. Organomet. Chem. 2010, 695, 82−89.
(17) Raja, N.; Raja, M. U.; Ramesh, R. Inorg. Chem. Commun. 2012,
19, 51−54.
(18) Bortoluzzi, M.; Paolucci, G.; Pitteri, B.; Zennaro, P.; Bertolasi, V.
J. Organomet. Chem. 2011, 696, 2565−2575.
+H). For 3,5-ditolylphenol (9b),36 oyster white solid, yield 99%; H
1
3
NMR (300 MHz, CDCl3): δ 7.52 (d, J = 8.1 Hz, 4H), 7.36 (s, 1H),
7.26 (d, 3J = 7.9 Hz, 4H), 7.01 (d, 4J = 1.4 Hz, 2H), 5.02 (s, 1H), 2.40
(s, 6H). 13C NMR (75 MHz, CDCl3): δ 156.1, 143.2, 137.9, 137.4,
129.5, 127.0, 118.6, 112.6, 21.1; LRMS (ESI): m/z (%) 275 (100)
(M++H), 316 (48) (M++CH3CN+H).
Gram-Scale Synthesis. A 50 mL reaction flask equipped with a
condenser was charged with a mixture of phenylboronic acid (15
mmol), 3,5-dibromophenol (5 mmol), anhydrous K2CO3 (30 mmol),
deionized water (20 mL), and 2.3 mg of 1 (5 × 10−3 mmol). The
outlet of the condenser was connected to a paraffin-filled bubble
counter. The mixture was heated at 115 °C, and continually stirred
until the consumption of aryl halide (monitoring with TLC). After
being cooled to the ambient temperature, it was diluted with water (20
mL), neutralized with 1 mol·L−1 HCl, and extracted with EtOAc
(three portions of 50 mL each). The combined organic phase was
washed with distilled water and saturated aqueous NaCl, dried over
anhydrous MgSO4, and then filtered and concentrated. The crude
product was purified by column chromatography (silica, hexane/
EtOAc mixture as eluent). The isolated coupling products were
(19) Kozlov, V. A.; Aleksanyan, D. V.; Nelyubina, Y. V.; Lyssenko, K.
A.; Petrovskii, P. V.; Vasil’ev, A. A.; Odinets, I. L. Organometallics
2011, 30, 2920−2932.
(20) Luo, Q.; Eibauer, S.; Reiser, O. J. Mol. Catal. A: Chem. 2007,
268, 65−69.
(21) Luo, Q.-L.; Tan, J.-P.; Li, Z.-F.; Qin, Y.; Ma, L.; Xiao, D.-R.
Dalton Trans. 2011, 40, 3601−3609.
(22) Xu, G.; Luo, Q.; Eibauer, S.; Rausch, A. F.; Stempfhuber, S.;
Zabel, M.; Yersin, H.; Reiser, O. Dalton Trans. 2011, 40, 8800−8806.
(23) The crystal data and experimental details of the structural
refinement for 1 and 2 are provided in the Supporting Information.
CCDC 862169 (1) and CCDC 853770 (2) contain the supplementary
crystallographic data for this publication. These data can be obtained
free of charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
1
confirmed by H NMR and 13C NMR. For 9a, yield, 94%; HPLC
purity, > 98.1%. For 9b, yield, 94%; HPLC purity, > 96.6%.
ASSOCIATED CONTENT
■
S
* Supporting Information
(24) Tu, T.; Malineni, J.; Dotz, K. H. Adv. Synth. Catal. 2008, 350,
̈
1
General experimental details, the crystal data for 1 and 2, H
1791−1795.
NMR, 13C NMR, and MS spectra for products. This material is
available free of charge via the Internet at http://pubs.acs.org.
(25) Tu, T.; Malineni, J.; Bao, X.; Dotz, K. H. Adv. Synth. Catal.
̈
2009, 351, 1029−1034.
(26) Hahn, F. E.; Jahnke, M. C.; Pape, T. Organometallics 2007, 26,
150−154.
(27) Garrett, C. E.; Prasad, K. Adv. Synth. Catal. 2004, 346, 889−900.
(28) Bolliger, J. L.; Frech, C. M. Adv. Synth. Catal. 2010, 352, 1075−
1080.
AUTHOR INFORMATION
Corresponding Author
*qlluo@swu.edu.cn, xiaodr98@yahoo.com.cn
■
Notes
(29) Wei, W.; Qin, Y.; Luo, M.; Xia, P.; Wong, M. S. Organometallics
The authors declare no competing financial interest.
2008, 27, 2268−2272.
(30) Bolliger, J. L.; Blacque, O.; Frech, C. M. Angew. Chem., Int. Ed.
2007, 46, 6514−6517.
ACKNOWLEDGMENTS
We are grateful to Prof. Fa-Jun Nan (Shanghai Institute of
Materia Medica, CAS, China) for help with elemental analysis.
■
(31) Bedford, R. B.; Draper, S. M.; Scully, P. N.; Welch, S. L. New J.
Chem. 2000, 24, 745−747.
8336
dx.doi.org/10.1021/jo3011733 | J. Org. Chem. 2012, 77, 8332−8337

The Journal of Organic Chemistry
Note
(32) Sheloumov, A. M.; Tundo, P.; Dolgushin, F. M.; Koridze, A. A.
Eur. J. Inorg. Chem. 2008, 572−576.
́
(33) Ines, B.; SanMartin, R.; Churruca, F.; Domínguez, E.; Urtiaga,
M. K.; Arriortura, M. I. Organometallics 2008, 27, 2833−2839.
(34) Lipke, M. C.; Woloszynek, R. A.; Ma, L.; Protasiewicz, J. D.
Organometallics 2009, 28, 188−196.
(35) Yorke, J.; Sanford, J.; Decken, A.; Xia, A. Inorg. Chim. Acta 2010,
363, 961−966.
(36) Heitman, L. H.; Narlawar, R.; de Vries, H.; Willemsen, M. N.;
Wolfram, D.; Brussee, J.; IJzerman, A. P. J. Med. Chem. 2009, 52,
2036−2042.
(37) Izawa, Y.; Pun, D.; Stahl, S. S. Science 2011, 333, 209−213.
(38) Li, Y.; Qin, Y.; Ma, L.; Tan, J.; Luo, Q. J. Southwest Univ. (Nat.
Sci. Ed.) 2011, 33 (5), 63−67.
(39) Takahashi, Y.; Ito, T.; Sakai, S.; Ishii, Y. J. Chem. Soc. D: Chem.
Commun. 1970, 1065−1066.
(40) Hoshiya, N.; Shimoda, M.; Yoshikawa, H.; Yamashita, Y.; Shuto,
S.; Arisawa, M. J. Am. Chem. Soc. 2010, 132, 7270−7272.
(41) Rosa, G. R.; Rosa, C. H.; Rominger, F.; Dupont, J.; Monteiro, A.
L. Inorg. Chim. Acta 2006, 359, 1947−1954.
(42) Bai, L.; Wang, J.-X. Adv. Synth. Catal. 2008, 350, 315−320.
(43) Aslam, S. N.; Stevenson, P. C.; Phythian, S. J.; Veitch, N. C.;
Hall, D. R. Tetrahedron 2006, 62, 4214−4226.
(44) Miguez, J. M. A.; Adrio, L. A.; Sousa-Pedrares, A.; Vila, J. M.;
Hii, K. K. J. Org. Chem. 2007, 72, 7771−7774.
(45) Ackermann, L.; Kapdi, A. R.; Fenner, S.; Kornhaaß, C.;
Schulzke, C. Chem.Eur. J. 2011, 17, 2965−2971.
8337
dx.doi.org/10.1021/jo3011733 | J. Org. Chem. 2012, 77, 8332−8337