Suzuki-Miyaura coupling of aryl sulfonates with arylboronic acids using a morpholine-Pd(OAc)2 catalyst system

Article abstract of DOI:10.1002/ejoc.201402120

We report a new catalyst system, a morpholine-Pd(OAc)₂ complex, for Suzuki-Miyaura coupling of aryl tosylates or mesylates with arylboronic acids to give biaryl compounds. The morpholine-Pd(OAc)₂ catalyst system is proposed to be a precursor of the catalytically active species in the coupling reaction. Aryl chlorides and aryl triflates can also be used in this coupling reaction. Altogether, 22 biaryl compounds were obtained using this catalyst system. We report a new catalyst system, a morpholine-Pd(OAc) ₂ complex, for Suzuki-Miyaura coupling of aryl tosylates or mesylates with arylboronic acids to give biaryl compounds. The morpholine-Pd(OAc) ₂ catalyst system is proposed to be a precursor of the catalytically active species in the coupling reaction. Copyright

Full text of DOI:10.1002/ejoc.201402120

FULL PAPER
DOI: 10.1002/ejoc.201402120
Suzuki–Miyaura Coupling of Aryl Sulfonates with Arylboronic Acids Using a
Morpholine–Pd(OAc)2 Catalyst System
Taichi Abe,*[a] Takashi Mino,*[a] Kohei Watanabe,[a] Fumitoshi Yagishita,[a] and
Masami Sakamoto[a]
Keywords: Homogeneous catalysis / Cross-coupling / C–C coupling / Palladium / Biaryls / N ligands
We report a new catalyst system, a morpholine–Pd(OAc)2
complex, for Suzuki–Miyaura coupling of aryl tosylates or
mesylates with arylboronic acids to give biaryl compounds.
The morpholine–Pd(OAc)2 catalyst system is proposed to be
a precursor of the catalytically active species in the coupling
reaction. Aryl chlorides and aryl triflates can also be used in
this coupling reaction. Altogether, 22 biaryl compounds were
obtained using this catalyst system.
to prepare, and their use is cost effective. DAPCy (5)[10c]
and diamine palladium complex 6[10e] have been used for
the Suzuki–Miyaura coupling of aryl halides (Figure 2). In
this paper, we report the application of a new morpholine-
Introduction
The Suzuki–Miyaura coupling reaction is an extremely
reliable method for the formation of C–C bonds on scales
from laboratory synthesis to industrial manufacturing. Nu-
merous procedures have been reported, and most large-
scale applications use aryl halides together with boronic
acid derivatives.[1] From the points of view of cost and
handling, tosylates and mesylates are promising candidates
for coupling partners, because they can be obtained from
inexpensive phenol derivatives and TsCl or MsCl. In ad-
dition, since almost all aryl tosylates and mesylates are crys-
talline, they are easy to purify and stable in storage.[2] In
fact, there are many reports of Suzuki–Miyaura coupling
reactions using aryl or alkenyl tosylates and aryl mesylates
catalysed by Ni,[3,4] Ru,[5] and Pd.[2,6–9] However, the re-
ported palladium-catalysed Suzuki–Miyaura coupling reac-
tions of aryl sulfonates use expensive phosphine ligands
(e.g., 1,[6a] 2,[6c] and 3[6d]). In addition, harsh conditions
above the solvent’s boiling point, and 2 equiv. of boronic
acid are normally required.[6a,6c,6d] On the other hand, ni-
trogen-based ligands such as amines,[10] N-heterocyclic
carbenes (NHC),[11] oximes,[12] hydrazones,[13] and others[14]
have been used in Suzuki–Miyaura coupling reactions with
aryl or alkenyl halides. Only one report exists, though, of
the use of nitrogen-based ligands with aryl tosylates or mes-
ylates: NHC-PdII-Im (4) was used by Shao (Figure 1).[15]
However, this procedure needs an expensive carbene-type
catalyst, morpholine as a solvent, and heating to 110–
130 °C for 24 h. On the other hand, amine ligands are easy
Figure 1. Ligands for Suzuki–Miyaura coupling reactions of aryl
tosylates.
[a] Department of Applied Chemistry and Biotechnology,
Graduate School of Engineering, Chiba University,
1-33, Yayoi-cho, Inage-ku, Chiba 263-8522, Japan
E-mail: t2-abe@hhc.eisai.co.jp
tmino@faculty.chiba-u.jp
http://chem.tf.chiba-u.jp/gacb06/index.html
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201402120.
Figure 2. Palladium complexes with amine ligands for Suzuki–
Miyaura coupling reactions.
Eur. J. Org. Chem. 2014, 3909–3916
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3909

T. Abe, T. Mino, K. Watanabe, F. Yagishita, M. Sakamoto
FULL PAPER
Pd(OAc)2 complex for the formation of biaryl compounds yield (Table 2, entry 3). When 1 mol-% of Pd(OAc)2 was
using aryl tosylates or mesylates togther with arylboronic used, the yield decreased to 55%, and when the reaction
acids at 80 °C.
was run under air the yield dropped to 38%. Other palla-
dium sources also gave good yields. PdCl2 in particular gave
almost the same yield as Pd(OAc)2 (Table 2, entries 6–8).
However, Pd2(dba)3 was not effective for this coupling reac-
tion (Table 2, entry 9). No amination products were ob-
served in any of these reactions.
Results and Discussion
First, we screened secondary amines using the coupling
reaction between 4-acetylphenyl tosylate (7) and 4-meth-
oxyphenylboronic acid (8). When morpholine was used, the
desired biaryl compound (i.e., 9) was obtained in a 92%
yield (Table 1, entry 1). We also attempted a lower equiva-
lence (250 mol-%) of morpholine, and other solvents (tert-
butyl alcohol and acetonitrile) for the reaction, but these
experiments only gave moderate yields (Table 1, entries 2–
4). Cyclic amines containing a second heteroatom gave
good yields (Table 1, entries 5–10), but the yield decreased
when piperidine or pyrrolidine was used (Table 1, entries 11
and 12). Aliphatic amines gave poor yields (Table 1, en-
tries 13 and 14). Finally, we tested dicyclohexylamine for
this reaction, which has been shown to be catalysed by
DAPCy (5).[10c] This gave a coupled compound in 19%
yield (Table 1, entry 15), which suggests that morpholine
might generate a highly reactive amine–palladium complex
for Suzuki–Miyaura coupling.
Table 2. Study of the palladium catalyst for the morpholine–palla-
dium-catalysed Suzuki–Miyaura coupling of aryl tosylates (acac =
acetylacetone; tfa = trifluoroacetate; dba = dibenzylideneace-
tone).[a]
Entry
Pd catalyst
Yield of 9a [%][b]
1
2
3
4
5
6
7
8
9
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
PdCl2
Pd(acac)2
Pd(tfa)2
Pd2(dba)3
92
26[c]
67[d]
55[e]
38[f]
89
80
71
1
Table 1. Optimization of the amine component for the amine–pal-
ladium-catalysed Suzuki–Miyaura coupling of aryl tosylates.[a]
[a] Reaction conditions: 4-acetylphenyl tosylate (7; 0.5 mmol), 4-
methoxyphenylboronic acid (8; 0.6 mmol), Pd catalyst (2.5 mol-%),
morpholine (2.5 mmol), K3PO4 (1.5 mmol), 2-propanol (1.5 mL),
N2, 80 °C, 2 h. [b] Yield from NMR spectroscopy with piperonal
as internal standard. [c] Na3PO4 was used as a base. [d] K2CO3 was
used as a base. [e] 1.0 mol-% of Pd(OAc)2 was used. [f] Reaction
was carried out in air for 14 h.
Entry
Amine
Yield of 9a [%][b]
Having optimized our reaction conditions, we explored
the scope of the morpholine–Pd(OAc)2 catalyst system for
the Suzuki–Miyaura coupling of arylboronic acids with aryl
tosylates.
1
2
3
4
5
6
7
8
morpholine
morpholine
morpholine
morpholine
thiomorpholine
N-methylpiperazine
N-methylpiperazine
N-methylpiperazine
N-ethylpiperazine
N-phenylpiperazine
piperidine
92
60[c]
66[d]
57[e]
53
The reaction was carried out using Pd(OAc)2 (2.5 mol-
%), morpholine (5.0 equiv.), and arylboronic acid
(1.2 equiv.). First, we clarified that using less arylboronic
acid (1.03 equiv.) gave 9a in almost the same yield as when
1.2 equiv. of arylboronic acid was used. The coupling reac-
tions proceeded in good yields with electron-rich or elec-
tron-withdrawing arylboronic acids to give 9b–9n. However,
the only examples of coupled products obtained from ortho-
substituted arylboronic acids were 9c, 9g, and 9j. A het-
eroarylboronic acid also coupled with 4-acetylphenyl tosyl-
ate to give 9o in good yield. When electron-rich 4-meth-
oxyphenyl tosylate was tested, the yield of 9p decreased to
20%. As had been seen with the regioisomeric arylboronic
acids, ortho- or meta-substituted aryl tosylates gave couping
products 9q and 9r in moderate yields. 2-Naphthyl tosylate
and 4-fluorophenyl tosylate gave the desired biaryl com-
80
69[d]
66[e]
73
9
10
11
12
13
14
15
72
62
58
39
27
19
pyrrolidine
di-n-propylamine
methylbenzylamine
dicyclohexylamine
[a] Reaction conditions: 4-acetylphenyl tosylate (7; 0.5 mmol), (4-
methoxyphenyl)boronic acid (8; 0.6 mmol), Pd(OAc)2 (2.5 mol-%),
amine (2.5 mmol), K3PO4 (1.5 mmol), 2-propanol (1.5 mL), N2,
80 °C, 2 h. [b] Yield from NMR spectroscopy with piperonal as
internal standard. [c] 250 mol-% of morpholine was used. [d] tert-
butyl alcohol was used as a solvent. [e] MeCN was used as a sol-
vent.
We also optimized the base and the palladium source. pounds (i.e., 9s and 9t). 5-(p-Tolylsulfonoxy)-1-indanone
When Na3PO4 was used as a base, the yield decreased also coupled in good yield to give 9u. Biphenyl indanone is
(Table 2, entry 2), and a reaction using K2CO3 gave a 67% an intermediate for the synthesis of pharmacologically
3910
www.eurjoc.org
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2014, 3909–3916

Suzuki–Miyaura Coupling Using Morpholine–Pd(OAc)2
Table 3. Scope and limitations of the morpholine–Pd(OAc)2 cata- active compounds, and this coupling method simplifies the
lyst system for the Suzuki–Miyaura coupling of aryl tosylates.[a]
preparation of this intermediate.[16] In addition, a het-
eroaryl tosylate compound was tested in the reaction, and
coupled compound 9v was obtained in moderate yield
(Table 3).
Next, we studied the coupling partners of the arylboronic
acid. 4-acetylphenyl mesylate was tested, and it reacted to
give the product in 56% yield using 5 mol-% of Pd(OAc)2
and tert-butyl alcohol as a solvent Ϫ 2-propanol gave a
poor yield (Table 4, entry 2). The triflate also reacted in to
give the product in good yield (Table 4, entry 3). The chlor-
ide was also tested, and it gave the product in high yield
(Table 4, entry 4). Thus, it is possible to use this new
method for the Suzuki–Miyaura coupling reactions of aryl
halides.
Table 4. Study of coupling partners for the morpholine–palladium-
catalysed Suzuki–Miyaura coupling of arylboronic acids.[a]
Entry
X
Yield of 9a [%][b]
1
2
3
4
OTs
OMs
OTf
Cl
92
56[c–e]
80[d,e]
93
[a] Reaction conditions: aryl coupling partner (0.5 mmol), (4-meth-
oxyphenyl)boronic acid (8; 0.6 mmol), Pd(OAc)2 (2.5 mol-%),
morpholine (2.5 mmol), K3PO4 (1.5 mmol), 2-propanol (1.5 mL),
N2, 80 °C, 2 h. [b] Yield from NMR spectroscopy (piperonal was
used as standard). [c] tert-butyl alcohol was used as a solvent.
[d] 5 mol-% of Pd(OAc)2 was used for the reaction. [e] Reaction was
carried out for 14 h.
Using our optimized reaction conditions for aryl tos-
ylates, we then tested the reactivity of aryl mesylates. Sev-
eral coupling reactions using electron-withdrawing aryl me-
sylates and electron-rich arylboronic acids were conducted.
These reactions gave almost the same yields for all examples
(Table 5).
To clarify the reaction mechanism, Pd(OAc)2 was treated
with morpholine in 2-propanol at 80 °C (Figure 3), and the
resulting crystalline 10 was analysed by single-crystal X-ray
analysis. We confirmed that the palladium centre was trans-
coordinated by two acetates and two nitrogen atoms of
morpholine to form a morpholine–Pd(OAc)2 catalyst sys-
tem (Figure 4).[17] We assume that a similar catalyst system
(morpholine–PdCl2) was generated when PdCl2 was used in
the optimization (Table 2, entry 6).[18] However, when 10
was used instead of Pd(OAc)2 and morpholine, a poor yield
was obtained (Table 6, entry 1). The addition of morpholine
allows the reaction to proceed (Table 6, entry 2), and no
significant difference was observed between this reaction
with 10 and a reaction using Pd(OAc)2 (Table 6, entry 3).
We assume that the coupling reaction is initiated by the
generation of the morpholine–Pd(OAc)2 species (i.e., 10).
[a] Reaction conditions: aryl tosylate (0.5 mmol), arylboronic acid
(0.6 mmol), Pd(OAc)2 (2.5 mol-%), morpholine (2.5 mmol), K3PO4
(1.5 mmol), 2-propanol (1.5 mL), N2, 80 °C, 14 h. [b] Reaction time
was 2 h. [c] 1.03 equiv. of arylboronic acid was used. [d] Yield from
NMR spectroscopy (piperonal was used as standard). [e] tert-Butyl
alcohol was used as a solvent.
Eur. J. Org. Chem. 2014, 3909–3916
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3911

T. Abe, T. Mino, K. Watanabe, F. Yagishita, M. Sakamoto
FULL PAPER
Table 5. Scope and limitations of the morpholine–Pd(OAc)2 cata- Then 10 is transformed into 12 (Figure 5), which acts as
lyst system for the Suzuki–Miyaura coupling of aryl mesylates.[a]
the active species. The generation of 11 under the reaction
conditions was also considered,[11a] but this was rejected
based on the result obtained in the absence of morpholine
(Table 6, entry 1). Further studies are needed to clarify the
reaction mechanism of the morpholine–Pd(OAc)2 catalyst
system.[19]
Table 6. Study of the active species in the morpholine–Pd(OAc)2
catalyst system.[a]
Entry
Catalyst
Morpholine [mol-%] Yield of 9a [%][b]
1
2
3
10
0
250
250
7
82
60
[a] Reaction conditions: aryl mesylate (0.5 mmol), arylboronic acid
(0.6 mmol), Pd(OAc)2 (5 mol-%), morpholine (2.5 mmol), K3PO4
(1.5 mmol), tert-butyl alcohol (1.5 mL), N2, 80 °C, 14 h. [b] Yield
from NMR spectroscopy (piperonal was used as standard).
10
Pd(OAc)2
[a] Reaction conditions: 4-acetylphenyl tosylate (7; 0.5 mmol), 4-
methoxyphenylboronic acid (8; 0.6 mmol), Pd catalyst (2.5 mol-%),
K3PO4 (1.5 mmol), 2-propanol (1.5 mL), N2, 80 °C, 2 h. [b] Yield
from NMR spectroscopy (piperonal was used as standard).
Figure 3. Synthesis of morpholine–Pd(OAc)2 complex 10.
Figure 5. Plausible active species in the morpholine–Pd(OAc)2 cata-
lyst system.
Conclusions
In summary, we have found a new Suzuki–Miyaura cou-
pling procedure using a morpholine–Pd(OAc)2 catalyst sys-
tem to generate biaryl compounds from aryl tosylates or
mesylates. This is the first application of the trans-type
amine-coordinated palladium catalyst. This easy procedure
is useful for large-scale reactions in the laboratory, and it
uses only inexpensive reagents. We also successfully
achieved coupling reactions using other sulfonates and
chloride as coupling partners.
Experimental Section
General Methods: Melting points were recorded with a melting-
point apparatus. 1H NMR spectra were recorded at 300 or
400 MHz. 13C NMR spectra were recorded at 75, 100, or 150 MHz,
Figure 4. ORTEP drawing of morpholine–Pd(OAc)2 complex 10
[solvent molecules (H2O) are omitted for clarity.].
3912
www.eurjoc.org
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2014, 3909–3916

Suzuki–Miyaura Coupling Using Morpholine–Pd(OAc)2
and the solvent peak was used as an internal reference. Electronic
impact (EI) mass spectra were recorded with a GC–MS instrument.
High-resolution mass spectra (HRMS) were recorded using the
electrospray ionization (ESI) method.
133.8, 131.2, 130.3, 128.4, 128.34, 128.32, 126.9, 126.4, 126.0,
125.5, 125.3, 26.7 ppm. MS (EI): m/z = 246 [M]+.
1-(2Ј-Methylbiphenyl-4-yl)ethanone (9c):[22] Following the general
procedure, using 4-acetylphenyl tosylate (0.50 mmol) and (2-meth-
ylphenyl)boronic acid (0.60 mmol), after 14 h at 80 °C, flash
chromatography (n-hexane/ethyl acetate, 15:1) gave compound 9c
(57.2 mg, 0.272 mmol, 54%) as a pale yellow oil. 1H NMR
(400 MHz, CDCl3): δ = 7.99 (d, J = 8.2 Hz, 2 H), 7.41 (d, J =
8.2 Hz, 2 H), 7.30–7.19 (m, 4 H), 2.63 (s, 3 H), 2.26 (s, 3 H) ppm.
13C NMR (100 MHz, CDCl3): δ = 197.8, 146.9, 140.7, 135.5, 135.1,
130.5, 129.44, 129.41, 128.2, 127.9, 125.9, 26.6, 20.4 ppm. MS (EI):
m/z = 210 [M]+.
General Procedure to Prepare Aryl Tosylates: Acetone (10 mL) was
added to a mixture of phenol (1.0 mmol), p-toluenesulfonyl chlor-
ide (1.05 mmol), and K2CO3 (1.1 mmol), and the mixture was
stirred at room temperature. After 5–24 h, the reaction mixture was
diluted with ethyl acetate and HCl (2 n aq.). The organic layer was
separated and washed with brine, then dried with MgSO4, and con-
centrated under reduced pressure. Hexane was added to the residue,
and the resulting suspension was stirred in an ice bath to give the
pure solid.
1-(3Ј-Methylbiphenyl-4-yl)ethanone (9d):[23] Following the general
procedure, using 4-acetylphenyl tosylate (0.50 mmol) and (3-meth-
ylphenyl)boronic acid (0.60 mmol), after 14 h at 80 °C, flash
chromatography (n-hexane/ethyl acetate, 15:1) gave compound 9d
(95.0 mg, 0.452 mmol, 90%) as a white solid, m.p. (hexane/ethyl
5-(p-Tolylsulfonyloxy)-1-indanone (9u): Acetone (7.5 mL) was
added to a mixture of 5-hydroxy-1-indanone (10 mmol), K2CO3
(11 mmol), and p-toluenesulfonylchloride (10.5 mmol), and the
mixture was stirred at room temperature for 24 h. The mixture was
diluted with ethyl acetate and HCl (2 n aq.). The organic layer was
washed with NaHCO3 (aq.) and brine, then dried with MgSO4.
The resulting solution was concentrated under reduced pressure to
give 5-p-toluenesulfonoxy-1-indanone (2.88 g, 9.53 mmol, 95%) as
1
acetate): 90–91 °C. H NMR (400 MHz, CDCl3): δ = 8.04 (d, J =
8.3 Hz, 2 H), 7.69 (d, J = 8.5 Hz, 2 H), 7.44 (d, J = 8.5 Hz, 2 H),
7.38 (t, J = 7.8 Hz, 1 H), 7.24 (d, J = 7.6 Hz, 1 H), 2.65 (s, 3 H),
2.45 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 197.7, 145.9,
139.8, 138.5, 135.7, 128.9, 128.8 (ϫ2), 128.0, 127.2, 124.3, 26.6,
21.5. MS (EI): m/z = 210 [M]+.
a
white solid, m.p. (ethyl acetate): 118–119 °C. 1H NMR
(400 MHz, CDCl3): δ = 7.74 (d, J = 7.8 Hz, 2 H), 7.66 (d, J =
8.3 Hz, 1 H), 7.34 (d, J = 7.9 Hz, 2 H), 7.25 (s, 1 H), 6.91–6.88 (m,
1 H), 3.12 (t, J = 5.4 Hz, 2 H), 2.73–2.69 (m, 2 H), 2.47 (s, 3 H)
ppm. 13C NMR (100 MHz, CDCl3): δ = 205.2, 156.9, 154.3, 145.8,
135.6, 132.1, 129.9, 128.4, 125.1, 121.7, 120.6, 36.3, 25.7, 21.7 ppm.
HRMS (ESI): calcd. for C16H15O4S [M + H]+ 303.0686; found
303.0675.
1-(4Ј-Methylbiphenyl-4-yl)ethanone (9e):[24] Following the general
procedure, using 4-acetylphenyl tosylate (0.50 mmol) and (4-meth-
ylphenyl)boronic acid (0.60 mmol), after 14 h at 80 °C, flash
chromatography (n-hexane/ethyl acetate, 15:1) gave compound 9e
(91.7 mg, 0.436 mmol, 87%) as a white solid, m.p. (hexane/ethyl
1
acetate): 118–119 °C. H NMR (400 MHz, CDCl3): δ = 8.03 (d, J
General Procedure for the Palladium–Morpholine-Catalysed Suzuki
Coupling of Aryl Tosylates with Arylboronic Acids: 2-Propanol
(1.5 mL) and morpholine (2.5 mmol) were added to a mixture of
Aryl tosylate (0.5 mmol), K3PO4 (1.5 mmol), Pd(OAc)2
(12.5 μmol), and arylboronic acid (0.6 mmol). The mixture was
stirred at 80 °C under a nitrogen atmosphere. After 2–14 h, the
mixture was diluted with ethyl acetate and HCl (2 n aq.; H2O was
used for compounds 9k, 9l, 9o, and 9v). The organic layer was
separated, and the aqueous layer was re-extracted with ethyl acet-
ate. The combined organic extracts were washed with brine, then
dried with MgSO4, and concentrated under reduced pressure. The
residue was purified by silica gel chromatography (hexane/ethyl
acetate).
= 7.9 Hz, 2 H), 7.68 (d, J = 9.3 Hz, 2 H), 7.55 (d, J = 7.1 Hz, 2
H), 7.29 (d, J = 7.7 Hz, 2 H), 2.64 (s, 3 H), 2.43 (s, 3 H) ppm. 13C
NMR (100 MHz, CDCl3): δ = 197.7, 145.6, 138.2, 136.9, 135.5,
129.6, 128.8, 127.0, 126.9, 26.6, 21.1 ppm. MS (EI): m/z = 210
[M]+.
1-(Biphenyl-4-yl)ethanone (9f):[25] Following the general procedure,
using 4-acetylphenyl tosylate (0.50 mmol) and phenylboronic acid
(0.60 mmol), after 14 h at 80 °C, flash chromatography (n-hexane/
ethyl acetate, 10:1) gave compound 9f (78.7 mg, 0.401 mmol, 80%)
as a white solid, m.p. (hexane/ethyl acetate): 118–119 °C. 1H NMR
(400 MHz, CDCl3): δ = 8.05 (d, J = 8.3 Hz, 2 H), 7.70 (d, J =
8.3 Hz, 2 H), 7.64 (d, J = 7.1 Hz, 2 H), 7.49 (t, J = 7.3 Hz, 2 H),
7.40 (t, J = 7.1 Hz, 1 H), 2.66 (s, 3 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 197.7, 145.8, 139.9, 135.8, 128.92, 128.88, 128.2,
127.24, 127.19, 26.6 ppm. MS (EI): m/z = 196 [M]+.
1-(4Ј-Methoxylbiphenyl-4-yl)ethanone (9a):[20] Following the general
procedure, using 4-acetylphenyl tosylate (0.50 mmol) and (4-meth-
oxyphenyl)boronic acid (0.60 mmol), after 2 h at 80 °C, flash
chromatography (n-hexane/ethyl acetate, 25:1) gave compound 9a
(99.6 mg, 0.440 mmol, 88%) as a white solid, m.p. (hexane/ethyl
1-(2Ј,4Ј-Dimethoxylbiphenyl-4-yl)ethanone (9g): Following the gene-
ral procedure, using 4-acetylphenyl tosylate (0.50 mmol) and 2,4-
methoxyphenylboronic acid (0.60 mmol), after 14 h at 80 °C, flash
chromatography (n-hexane/ethyl acetate, 10:1) gave compound 9g
(75.4 mg, 0.294 mmol, 59%) as a white solid, m.p. (hexane/ethyl
1
acetate): 152–153 °C. H NMR (400 MHz, CDCl3): δ = 8.01 (d, J
= 8.5 Hz, 2 H), 7.65 (d, J = 8.3 Hz, 2 H), 7.59 (d, J = 8.8 Hz, 2
H), 7.01 (d, J = 8.8 Hz, 2 H), 3.87 (s, 3 H), 2.64 (s, 3 H) ppm. 13C
NMR (100 MHz, CDCl3): δ = 197.7, 159.9, 145.3, 135.2, 132.2,
128.9, 128.3, 126.5, 114.3, 55.3, 26.6 ppm. MS (EI): m/z = 226
[M]+.
2-(4Ј-Ethanoylphenyl)naphthalene (9b):[21] Following the general
procedure, using 4-acetylphenyl tosylate (0.50 mmol) and (1-naph-
thyl)boronic acid (0.60 mmol), after 2 h at 80 °C, flash chromatog-
raphy (n-hexane/ethyl acetate, 10:1) gave compound 9b (92.4 mg,
0.375 mmol, 75%) as a white solid, m.p. (hexane/ethyl acetate):
103–104 °C. 1H NMR (400 MHz, CDCl3): δ = 8.11 (d, J = 8.3 Hz,
1
acetate): 97–98 °C. H NMR (400 MHz, CDCl3): δ = 7.99 (d, J =
8.5 Hz, 2 H), 7.62 (d, J = 8.5 Hz, 2 H), 7.28 (d, J = 8.3 Hz, 1 H),
6.62–6.57 (m, 2 H), 3.87 (s, 3 H), 3.82 (s, 3 H), 2.63 (s, 3 H) ppm.
13C NMR (100 MHz, CDCl3): δ = 197.8, 160.9, 157.5, 143.4, 134.9,
131.2, 129.4, 128.0, 122.1, 104.8, 98.9, 55.4, 55.3, 26.5 ppm. HRMS
(ESI): calcd. for C16H16O3Na [M + Na]+ 279.0992; found 279.0987.
1-[3Ј,4Ј-(Methylenedioxy)biphenyl-4-yl]ethanone (9h):[26] Following
the general procedure, using 4-acetylphenyl tosylate (0.50 mmol)
and (3,4-methylendioxyphenyl)boronic acid (0.60 mmol), after 14 h
2 H), 7.96–7.89 (m, 2 H), 7.86 (d, J = 9.0 Hz, 1 H), 7.62 (d, J = at 80 °C, flash chromatography (n-hexane/ethyl acetate, 10:1) gave
8.8 Hz, 2 H), 7.58–7.50 (m, 2 H), 7.50–7.42 (m, 2 H), 2.70 (s, 3 H)
compound 9h (118.2 mg, 0.492 mmol, 98%) as a white solid, m.p.
ppm. 13C NMR (100 MHz, CDCl3): δ = 197.8, 145.8, 139.0, 136.0,
(hexane/ethyl acetate): 132–133 °C. 1H NMR (400 MHz, CDCl3):
Eur. J. Org. Chem. 2014, 3909–3916
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3913

T. Abe, T. Mino, K. Watanabe, F. Yagishita, M. Sakamoto
FULL PAPER
δ = 8.01 (d, J = 8.3 Hz, 2 H), 7.62 (d, J = 8.5 Hz, 2 H), 7.15–7.11
and 6.0 Hz), 117.8 (d, JC,F = 16.5 Hz), 116.3 (d, JC,F = 16.5 Hz),
(m, 2 H), 6.92 (d, J = 7.6 Hz, 1 H), 6.04 (s, 2 H), 2.64 (s, 3 H) 26.7 ppm. HRMS (ESI): calcd. for C14H11OF2 [M + H]+ 233.0772;
ppm. 13C NMR (100 MHz, CDCl3): δ = 197.8, 148.3, 147.9, 145.4,
135.4, 134.0, 128.9, 126.8, 121.0, 108.7, 107.5, 101.3, 26.6 ppm. MS
(EI): m/z = 240 [M]+.
found 233.0775.
5-(4-Acetylphenyl)-2-methoxypyridine (9o): Following the general
procedure, using 4-acetylphenyl tosylate (0.50 mmol), 2-methoxy-
5-pyridineboronic acid (0.60 mmol), and tert-butyl alcohol as a sol-
vent, after 14 h at 80 °C, flash chromatography (n-hexane/ethyl
acetate, 7.5:1) gave compound 9o (87.0 mg, 0.383 mmol, 77%) as
a white solid, m.p. (hexane/ethyl acetate): 108–109 °C. 1H NMR
(400 MHz, CDCl3): δ = 8.44 (d, J = 2.0 Hz, 1 H), 8.04 (d, J =
8.8 Hz, 2 H), 7.83 (dd, J = 2.6, 8.7 Hz, 1 H), 7.63 (d, J = 8.5 Hz,
2 H), 6.85 (d, J = 8.1 Hz, 1 H), 4.00 (s, 3 H), 2.64 (s, 3 H) ppm.
13C NMR (100 MHz, CDCl3): δ = 197.5, 164.2, 145.3, 142.5, 137.3,
135.8, 129.1, 128.7, 126.6, 111.1, 53.7, 26.6 ppm. HRMS (ESI):
calcd. for C14H14NO2 [M + H]+ 228.1019; found 228.1017.
1-(4Ј-tert-Butylbiphenyl-4-yl)ethanone (Table 3, 9i): Following the
general procedure, using 4-acetylphenyl tosylate (0.50 mmol) and
(4-tert-butylphenyl)boronic acid (0.60 mmol), after 14 h at 80 °C,
flash chromatography (n-hexane/ethyl acetate, 10:1) gave com-
pound 9i (96.5 mg, 0.382 mmol, 77%) as as a white solid, m.p. (hex-
ane/ethyl acetate): 128–129 °C. 1H NMR (400 MHz, CDCl3): δ =
8.04 (d, J = 8.1 Hz, 2 H), 7.71 (d, J = 8.1 Hz, 2 H), 7.60 (d, J =
7.5 Hz, 2 H), 7.52 (d, J = 7.6 Hz, 2 H), 2.65 (s, 3 H), 1.40 (s, 9 H)
ppm. 13C NMR (100 MHz, CDCl3): δ = 197.7, 151.4, 145.5, 136.8,
135.5, 128.9, 126.92, 126.86, 125.9, 34.6, 31.3, 26.6 ppm. HRMS
(ESI): calcd. for C18H21O [M + H]+ 253.1587; found 253.1580.
1-Methoxy(4Ј-tert-butylphenyl-4-yl)benzene (9p):[20] Following the
general procedure, using 4-methoxyphenyl tosylate (0.50 mmol)
and (4-tert-butylphenyl)boronic acid (0.60 mmol), after 14 h at
80 °C, flash chromatography (n-hexane/ethyl acetate, 25:1, then
10:1) gave compound 9p (24.3 mg, 0.101 mmol, 20%) as a white
solid, m.p. (hexane/ethyl acetate): 136–137 °C. 1H NMR (400 MHz,
CDCl3): δ = 7.59–7.50 (m, 4 H), 7.50–7.45 (m, 2 H), 7.00 (d, J =
9.0 Hz, 2 H), 3.87 (s, 3 H), 1.39 (s, 9 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 158.9, 149.6, 137.9, 133.6, 128.0, 126.4, 125.6, 114.1,
55.3, 34.5, 31.4 ppm. MS (EI): m/z = 240 [M]+.
1-[4Ј-(N-tert-Butylcarbamate)biphenyl-4-yl]ethanone (9k): Follow-
ing the general procedure, using the 4-acetylphenyl tosylate
(0.50 mmol) and [4-(N-tert-butylcarbamate)phenyl]boronic acid
(0.60 mmol), after 14 h at 80 °C, flash chromatography (n-hexane/
ethyl acetate, 5:1) gave compound 9k (115.4 mg, 0.371 mmol, 74%)
as a white solid, m.p. (hexane/ethyl acetate): 183–184 °C. 1H NMR
(400 MHz, CDCl3): δ = 8.01 (d, J = 7.8 Hz, 2 H), 7.66 (d, J =
8.5 Hz, 2 H), 7.57 (d, J = 8.5 Hz, 2 H), 7.47 (d, J = 8.3 Hz, 2 H),
6.63 (br. s, 1 H), 2.64 (s, 3 H), 1.55 (s, 9 H) ppm. 13C NMR
(150 MHz, CDCl3): δ = 197.8, 152.6, 145.2, 138.6, 135.5, 134.3,
128.9, 127.8, 126.7, 118.8, 80.8, 28.3, 26.6 ppm. HRMS (ESI):
calcd. for C19H21O3NNa [M + Na]+ 334.1414; found 334.1407.
1-(4Ј-Methoxybiphenyl-2-yl)ethanone (9q):[28] Following the general
procedure, using 2-acetylphenyl tosylate (0.50 mmol) and (4-meth-
oxyphenyl)boronic acid (0.60 mmol), after 14 h at 80 °C, flash
chromatography (n-hexane/ethyl acetate, 15:1) gave compound 9q
(61.1 mg, 0.270 mmol, 54%) as a pale yellow oil. 1H NMR
(400 MHz, CDCl3): δ = 7.53–7.51 (m, 1 H), 7.49–7.46 (m, 1 H),
7.39–7.36 (m, 2 H), 7.26 (d, J = 8.8 Hz, 2 H), 6.96 (d, J = 8.8 Hz,
2 H), 3.85 (s, 3 H), 2.02 (s, 3 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 205.2, 159.5, 140.9, 140.1, 133.0, 130.6, 130.1, 129.9,
127.7, 127.0, 114.1, 55.3, 30.4 ppm. MS (EI): m/z = 226 [M]+.
1-[3Ј-(N-tert-Butylcarbamate)biphenyl-4-yl]ethanone (9l): Following
the general procedure, using 4-acetylphenyl tosylate (0.50 mmol)
and [3-(N-tert-butylcarbamate)phenyl]boronic acid (0.60 mmol),
after 14 h at 80 °C, flash chromatography (n-hexane/ethyl acetate,
10:1) gave compound 9l (113.2 mg, 0.364 mmol, 73%) as a white
solid, m.p. (hexane/ethyl acetate): 150–151 °C. 1H NMR (400 MHz,
CDCl3): δ = 8.02 (d, J = 7.9 Hz, 2 H), 7.75 (s, 1 H), 7.69 (d, J =
8.3 Hz, 2 H), 7.39 (t, J = 7.1 Hz, 1 H), 7.36–7.28 (m, 2 H), 6.63
(br. s, 1 H), 2.65 (s, 3 H), 1.54 (s, 9 H) ppm. 13C NMR (150 MHz,
CDCl3): δ = 197.9, 152.8, 145.5, 140.8, 139.1, 136.0, 129.5, 128.9,
127.3, 121.9, 118.3, 117.3, 80.7, 28.4, 26.7 ppm. HRMS (ESI):
calcd. for C19H21O3NNa [M + Na]+ 334.1414; found 334.1404.
1-(4Ј-Fluorobiphenyl-4-yl)ethanone (9m):[27] Following the general
procedure, using 4-acetylphenyl tosylate (0.50 mmol) and (3-fluo-
rophenyl)boronic acid (0.60 mmol), after 14 h at 80 °C, flash
chromatography (n-hexane, then n-hexane/ethyl acetate, 20:1, then
10:1) gave compound 9m (88.0 mg, 0.411 mmol, 82%) as a white
solid, m.p. (hexane/ethyl acetate): 103–104 °C. 1H NMR (400 MHz,
CDCl3): δ = 8.04 (d, J = 8.1 Hz, 2 H), 7.58–7.67 (m, 4 H), 7.17 (t,
J = 8.1 Hz, 2 H), 2.65 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3):
1-(4Ј-Methoxybiphenyl-3-yl)ethanone (9r):[29] Following the general
procedure, using 3-acetylphenyl tosylate (0.50 mmol) and (4-meth-
oxyphenyl)boronic acid (0.60 mmol), after 14 h at 80 °C, flash
chromatography (n-hexane/ethyl acetate, 15:1) gave compound 9r
(66.6 mg, 0.294 mmol, 59%) as a white solid, m.p. (hexane/ethyl
acetate): 57–58 °C. 1H NMR (400 MHz, CDCl3): δ = 8.15 (s, 1 H),
7.89 (d, J = 7.6 Hz, 1 H), 7.75 (d, J = 7.3 Hz, 1 H), 7.57 (d, J =
8.8 Hz, 2 H), 7.51 (t, J = 7.6 Hz, 1 H), 7.01 (d, J = 8.5 Hz, 2 H),
3.88 (s, 3 H), 2.67 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ
= 198.1, 159.5, 141.2, 137.6, 132.6, 131.2, 128.9, 128.2, 126.5, 126.4,
114.3, 55.3, 26.7 ppm. MS (EI): m/z = 226 [M]+.
2-(4Ј-Methoxyphenyl)naphthalene (9s):[30] Following the general
procedure, using 2-naphthyl tosylate (0.50 mmol) and (4-meth-
oxyphenyl)boronic acid (0.60 mmol), after 14 h at 80 °C, flash
chromatography (n-hexane/ethyl acetate, 15:1) gave compound 9s
(97.6 mg, 0.417 mmol, 83%) as a white solid, m.p. (hexane/ethyl
δ = 197.6, 162.9 (d, JC,F = 248.0 Hz), 144.6, 135.9 (d, JC,F
=
4.1 Hz), 135.8, 128.91, 128.86 (d, JC,F = 8.3 Hz), 127.0, 115.8 (d,
JC,F = 21.6 Hz), 26.6 ppm. MS (EI): m/z = 214 [M]+.
1-(3Ј,4Ј-Difluorobiphenyl-4-yl)ethanone (9n): Following the general
procedure, using 4-acetylphenyl tosylate (0.50 mmol) and (3,4-
fluorophenyl)boronic acid (0.60 mmol), after 14 h at 80 °C, flash
chromatography (n-hexane/ethyl acetate, 20:1, then 10:1) gave com-
pound 9n (96.3 mg, 0.415 mmol, 83%) as a white solid, m.p. (hex-
ane/ethyl acetate): 75–76 °C. 1H NMR (400 MHz, CDCl3): δ = 8.02
(d, J = 6.3 Hz, 2 H), 7.60 (d, J = 6.8 Hz, 2 H), 7.45–7.37 (m, 1 H),
7.37–7.30 (m, 1 H), 7.30–7.19 (m, 1 H), 2.62 (s, 3 H) ppm. 13C
NMR (150 MHz, CDCl3): δ = 197.6, 151.4 (dd, JC,F = 13.5,
18.8 Hz), 149.7 (dd, JC,F = 13.5, and 19.5 Hz), 143.6, 137.0 (dd,
1
acetate): 130–131 °C. H NMR (400 MHz, CDCl3): δ = 8.04 (s, 1
H), 7.96–7.88 (m, 3 H), 7.77 (d, J = 8.5 Hz, 1 H), 7.71 (d, J =
8.8 Hz, 2 H), 7.57–7.48 (m, 2 H), 7.07 (d, J = 9.0 Hz, 2 H), 3.91
(s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 159.2, 138.1,
133.7, 133.6, 132.3, 128.4, 128.3, 128.0, 127.6, 126.2, 125.6, 125.4,
125.0, 114.3, 55.3 ppm. MS (EI): m/z = 234 [M]+.
1-Fluoro(4Ј-methoxyphenyl-4-yl)benzene (9t):[31] Following the ge-
neral procedure, using 4-fluorophenyl tosylate (0.50 mmol) and (4-
methoxyphenyl)boronic acid (0.60 mmol), after 14 h at 80 °C, flash
JC,F = 4.5 and 6.8 Hz), 136.3, 129.1, 127.1, 123.3 (dd, JC,F = 3.0 chromatography (n-hexane/ethyl acetate, 20:1) gave compound 9t
3914
www.eurjoc.org
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2014, 3909–3916

Suzuki–Miyaura Coupling Using Morpholine–Pd(OAc)2
(53.0 mg, 0.262 mmol, 52%) as a white solid, m.p. (hexane/ethyl (s, 2 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 162.2 (d, JC,F
=
acetate): 90–91 °C. 1H NMR (400 MHz, CDCl3): δ = 7.56–7.46 (m, 245.5 Hz), 148.1, 147.0, 137.1 (d, JC,F = 3.3 Hz), 134.6, 128.4 (d,
4 H), 7.16–7.09 (m, 2 H), 7.02–6.97 (m, 2 H), 3.87 (s, 3 H) ppm. JC,F = 8.3 Hz), 120.5, 115.5 (d, JC,F = 21.6 Hz), 108.6, 107.6,
13C NMR (100 MHz, CDCl3): δ = 162.1 (d, JC,F = 245.5 Hz),
159.1, 136.9 (d, JC,F = 3.3 Hz), 132.8, 128.2 (d, JC,F = 8.3 Hz),
128.0, 115.5 (d, JC,F = 20.7 Hz), 114.2, 55.3 ppm. MS (EI): m/z =
202 [M]+.
101.2 ppm. MS (EI): m/z = 216 [M]+.
Synthesis of Morpholine-Pd(OAc)2 Complex 10:[17] 2-Propanol
(10 mL) was added to a mixture of Pd(OAc)2 (1.0 mmol) and
morpholine (2.0 mmol), and the mixture was heated to 80 °C for
2 h under a nitrogen atmosphere. Then the reaction mixture was
allowed to stand for 13 d, and the resulting crystalline solid was
5-(4-Methoxyphenyl)-2,3-dihydroindene-1-one (9u):[16a] Following
the general procedure, using 5-(p-tolylsulfonoxy)-1-indanone
(0.50 mmol) and (4-methoxyphenyl)boronic acid (0.60 mmol), after collected by filtration to give compound 10 (107.0 mg, 0.246 mmol,
14 h at 80 °C, flash chromatography (n-hexane/ethyl acetate, 10:1)
gave compound 9u (84.6 mg, 0.355 mmol, 71%) as a white solid,
m.p. (hexane/ethyl acetate): 153–154 °C. 1H NMR (400 MHz,
CDCl3): δ = 7.80 (d, J = 8.1 Hz, 1 H), 7.63 (s, 1 H), 7.62–7.53 (m,
25%) as yellow crystals, m.p. (2-propanol): 140–142 °C (decom-
posed). 1H NMR (300 MHz, DMSO): δ = 5.60–5.53 (m, 2 H),
3.58–3.38 (m, 8 H), 2.79–2.64 (m, 8 H), 1.82 (s, 6 H) ppm. 13C
NMR (75 MHz, DMSO): δ = 177.7, 65.9, 48.6, 24.0 ppm. HRMS
3 H), 7.01 (d, J = 7.9 Hz, 2 H), 3.87 (s, 3 H), 3.18 (t, J = 6.3 Hz, (ESI): calcd. for C12H25O6N2Pd [M + H]+ 399.0742; found
2 H), 2.76–2.70 (m, 2 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 399.0734.
206.5, 160.0, 155.9, 147.2, 135.4, 132.5, 128.6, 126.2, 124.4, 124.0,
Supporting Information (see footnote on the first page of this arti-
cle): Characterization data and copies of the NMR spectra of the
114.4, 55.4, 36.5, 25.8 ppm. MS (EI): m/z = 238 [M]+.
6-(4-Methoxyphenyl)quinoline (9v):[32] Following the general pro-
cedure, using 6-quinoline tosylate (0.50 mmol) and (4-meth-
oxyphenyl)boronic acid (0.60 mmol), after 14 h at 80 °C, flash
chromatography (n-hexane/ethyl acetate, 5:1, then n-hexane/ethyl
acetate, 3:1) gave compound 9v (72.2 mg, 0.307 mmol, 61%) as a
white solid, m.p. (hexane/ethyl acetate): 108–109 °C. 1H NMR
(400 MHz, CDCl3): δ = 8.91 (dd, J = 1.7, 4.1 Hz, 1 H), 8.24–8.15
(m, 2 H), 7.99–7.91 (m, 2 H), 7.65 (d, J = 8.8 Hz, 2 H), 7.43–7.37
(m, 1 H), 7.03 (d, J = 8.8 Hz, 2 H), 3.87 (s, 3 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 159.5, 149.8, 147.1, 138.9, 136.3, 132.6,
129.5, 129.1, 128.5, 128.4, 124.5, 121.3, 114.4, 55.3 ppm. MS (EI):
m/z = 235 [M]+.
products.
Acknowledgments
Reagents and laboratory equipments were provided from Eisai Co.,
Ltd. for this study. The authors thank the members of API re-
search, CMC, Japan for their helpful support.
[1] J. Magano, J. R. Dunetz, Chem. Rev. 2011, 111, 2177–2250.
[2] C. M. So, F. Y. Kwong, Chem. Soc. Rev. 2011, 40, 4963–4972.
[3] For selected examples of Ni-catalysed Suzuki–Miyaura cou-
pling with aryl mesylates and tosylates, see: a) V. Percec, J. Y.
Bae, D. H. Hill, J. Org. Chem. 1995, 60, 1060–1065; b) V. Per-
cec, G. M. Golding, J. Smidrkal, O. Weichold, J. Org. Chem.
2004, 69, 3447–3452; c) B. H. Lipshutz, T. Butler, E. Swift, Org.
Lett. 2008, 10, 697–699; d) K. W. Quasdorf, M. Reiner, K. V.
Petrova, N. K. Garg, J. Am. Chem. Soc. 2009, 131, 17748–
17749; e) K. W. Quasdorf, A. Antoft-Finch, P. Liu, A. L. Silb-
erstein, A. Komaromi, T. Blackburn, S. D. Ramgren, K. N.
Houk, V. Snieckus, N. K. Garg, J. Am. Chem. Soc. 2011, 133,
6352–6363; f) M. Baghbanzadeh, C. Pilger, C. O. Kappe, J.
Org. Chem. 2011, 76, 1507–1510.
[4] For selected review of Ni-catalysed Suzuki–Miyaura coupling
with aryl mesylates and tosylates, see: a) B. M. Rosen, K. W.
Quasdorf, D. A. Wilson, N. Zhang, A. M. Resmerita, N. K.
Garg, V. Percec, Chem. Rev. 2011, 111, 1346–1416; b) T. Mes-
ganaw, N. K. Garg, Org. Process Res. Dev. 2013, 17, 29–39; c)
D.-G. Yu, B.-J. Li, Z.-J. Shi, Acc. Chem. Res. 2010, 43, 1486–
1495.
[5] a) J. Wu, L. Zhang, Y. Luo, Tetrahedron Lett. 2006, 47, 6747–
6750; b) J. Wu, L. Zhang, K. Gao, Eur. J. Org. Chem. 2006,
5260–5263; c) L. Zhang, J. Wu, Adv. Synth. Catal. 2008, 350,
2409–2413.
[6] For selected examples of Pd-catalysed Suzuki–Miyaura cou-
pling with aryl tosylate, see: a) H. N. Nguyen, X. Huang, S. L.
Buchwald, J. Am. Chem. Soc. 2003, 125, 11818–11819; b) L.
Zhang, T. Meng, J. Wu, J. Org. Chem. 2007, 72, 9346–9349; c)
C. M. So, C. P. Lau, A. S. C. Chan, F. Y. Kwong, J. Org. Chem.
2008, 73, 7731–7734; d) B. Bhayana, B. P. Fors, S. L. Buchwald,
Org. Lett. 2009, 11, 3954–3957.
General Procedure for the Study of Coupling Partners for Morph-
oline–Palladium-Catalysed Suzuki–Miyaura Coupling of Aryl-
boronic Acids: 2-Propanol (1.5 mL) and morpholine (2.5 mmol)
were added to a mixture of aryl coupling partner (0.5 mmol),
K3PO4 (1.5 mmol), Pd(OAc)2 (12.5 μmol), and arylboronic acid
(0.6 mmol). The mixture was stirred at 80 °C under a nitrogen at-
mosphere. After 2 h, the mixture was diluted with ethyl acetate and
HCl (2 n aq.). The organic layer was separated, and aqueous layer
was re-extracted with ethyl acetate. The combined organic extracts
were washed with brine, then dried with MgSO4, and concentrated
under reduced pressure. The yield was calculated from the NMR
spectrum using piperonal as an internal standard.
General Procedure for Palladium–Morpholine-Catalysed Suzuki
Coupling of Aryl Mesylates with Arylboronic Acids: tert-Butyl
alcohol (1.5 mL) and morpholine (2.5 mmol) were added to a mix-
ture of aryl mesylate (0.5 mmol), K3PO4 (1.5 mmol), Pd(OAc)2
(25.0 μmol), and arylboronic acid (0.6 mmol). The mixture was
stirred at 80 °C under a nitrogen atmosphere. After 14 h, the mix-
ture was diluted with ethyl acetate and HCl (2 n aq.). The organic
layer was separated, and aqueous layer was re-extracted with ethyl
acetate. The combined organic extracts were washed with brine,
then dried with MgSO4, and concentrated under reduced pressure.
The residue was purified by silica gel chromatography (hexane/ethyl
acetate).
1-Fluoro-[3Ј,4Ј-(methylenedioxy)phenyl-4-yl]benzene (9w):[33] Fol-
lowing the general procedure, using 4-fluorophenyl mesylate
[7] For selected reviews of Pd-catalysed Suzuki–Miyaura coupling
with aryl tosylate, see: a) B. J. Li, D. G. Yu, C. L. Sun, Z. J.
Shi, Chem. Eur. J. 2011, 17, 1728–1759.
[8] For selected examples of Pd-catalysed Suzuki–Miyaura cou-
pling with alkenyl tosylate, see: a) J. Wu, Q. Zhu, L. Wang, R.
Fathi, Z. Yang, J. Org. Chem. 2003, 68, 670–673; b) D. Stein-
huebel, J. M. Baxter, M. Palucki, I. W. Davies, J. Org. Chem.
2005, 70, 10124–10127; c) T. E. Jacks, D. T. Belmont, C. A.
(0.50 mmol)
and
(3,4-methylendioxyphenyl)boronic
acid
(0.60 mmol), after 14 h at 80 °C, flash chromatography (n-hexane,
then n-hexane/ethyl acetate, 10:1) gave compound 9w (57.5 mg,
0.266 mmol, 53%) as a white solid, m.p. (hexane/ethyl acetate): 57–
58 °C. 1H NMR (400 MHz, CDCl3): δ = 7.49–7.45 (m, 2 H), 7.13–
7.08 (m, 2 H), 7.02–7.00 (m, 2 H), 6.88 (d, J = 8.1 Hz, 1 H), 6.01
Eur. J. Org. Chem. 2014, 3909–3916
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3915

T. Abe, T. Mino, K. Watanabe, F. Yagishita, M. Sakamoto
FULL PAPER
Briggs, N. M. Horne, G. D. Kanter, G. L. Karrick, J. J. Krikke, [15]
R. J. McCabe, J. G. Mustakis, T. N. Nanninga, G. S. Rise-
Z.-Y. Wang, G.-Q. Chen, L. X. Shao, J. Org. Chem. 2012, 77,
6608–6614.
dorph, R. E. Seamans, R. Skeean, D. D. Winkle, T. M. Zennie,
Org. Process Res. Dev. 2004, 8, 201–212; d) L. Zhang, T. Meng,
R. Fan, J. Wu, J. Org. Chem. 2007, 72, 7279–7286; e) T. M.
Gøgsig, L. S. Søbjerg, A. T. Lindhardt, K. L. Jensen, T.
Skrydstrup, J. Org. Chem. 2008, 73, 3404–3410; f) H. Nakat-
suji, H. Nishikado, K. Ueno, Y. Tanabe, Org. Lett. 2009, 11,
4258–4261; g) H. Zhang, C. B. Zhou, Q. Y. Chen, J. C. Xiao,
R. Hong, Org. Lett. 2010, 12, 560–563; h) M. Luthy, R. J. K.
Taylor, Tetrahedron Lett. 2012, 53, 3444–3447.
[16]
a) M. D. Chordia, M. Zigler, L. J. Murphree, H. Figler, T. L.
Macdonald, R. A. Olsson, J. Linden, J. Med. Chem. 2005, 48,
5131–5139; b) G. M. Allan, N. Vicker, H. R. Lawrence, H. J.
Tutill, J. M. Day, M. Huchet, E. Ferrandis, M. J. Reed, A. Pu-
rohit, B. V. L. Potter, Bioorg. Med. Chem. 2008, 16, 4438–4456;
c) M. A. Pinto-Bazurco Mendieta, M. Negri, C. Jagusch, U.
Muller-Vieira, T. Lauterbach, R. W. Hartmann, J. Med. Chem.
2008, 51, 5009–5018.
This crystal had already isolated: O. N. Shishilov, T. A. Strom-
nova, A. V. Churakov, L. G. Kuz’mina, I. A. Efimenko, Russian
Journal of Inorganic Chemistry 2006, 51, 574–580, but it had
not been used in Suzuki–Miyaura coupling reactions. CCDC-
987557 (for 10) contain the supplementary crystallographic
data for this paper. These data can be obtained free of charge
from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
[17]
[9] For selected examples of Pd-catalysed Suzuki–Miyaura cou-
pling with aryl mesylates, see: a) C. M. So, C. P. Lau, F. Y.
Kwong, Angew. Chem. Int. Ed. 2008, 47, 8059–8063; Angew.
Chem. 2008, 120, 8179–8183; b) J. Kuroda, K. Inamota, K.
Hiroya, T. Doi, Eur. J. Org. Chem. 2009, 2251–2261; c) B. Bhay-
ana, B. P. Fors, S. L. Buchwald, Org. Lett. 2009, 11, 3954–3957;
d) W. K. Chow, C. M. So, C. P. Lau, F. Y. Kwong, J. Org.
Chem. 2010, 75, 5109–5112; e) G. A. Molander, F. Beaumard,
Org. Lett. 2011, 13, 1242–1245; f) K.-H. Chung, C.-M. So, S.-
M. Wong, C.-H. Luk, Z. Zhou, C.-P. Lau, F. Y. Kwong, Chem.
Commun. 2012, 48, 1967–1969.
[10] a) B. Tao, D. W. Boykin, Tetrahedron Lett. 2003, 44, 7993–
7996; b) J.-H. Li, W.-J. Liu, Org. Lett. 2004, 6, 2809–2811; c)
B. Tao, D. W. Boykin, J. Org. Chem. 2004, 69, 4330–4335; d)
Y.-X. Xie, J.-H. Li, D. L. Yin, J. Org. Chem. 2006, 26, 1155–
1163; e) L. Chahen, B. Therrien, G. Süss-Fink, Eur. J. Inorg.
Chem. 2007, 5045–5051; f) K. Karami, M. M. Salah, Appl. Or-
ganomet. Chem. 2010, 24, 828–832; g) P. Das, C. Sarmah, A.
Tairai, U. Bora, Appl. Organomet. Chem. 2011, 25, 283–288.
[11] a) O. Navarro, R. A. Kelly, S. P. Nolan, J. Am. Chem. Soc.
2003, 125, 16194–16195; b) R. Singh, M. S. Viciu, N. Kramar-
eva, O. Navarro, S. P. Nolan, Org. Lett. 2005, 7, 1829–1832; c)
[18]
[19]
[20]
[21]
[22]
[23]
R. B. Singh, S. Mitra, P. Kundu, Thermochim. Acta 1996, 285,
191–197.
DAPCy also confirmed that it was not a real active species, see
ref.[10c]
N. Hoshiya, M. Shimoda, H. Yoshikawa, Y. Yamashita, S.
Shuto, M. Arisawa, J. Am. Chem. Soc. 2010, 132, 7270–7272.
G. A. Molander, F. Beaumard, J. Am. Chem. Soc. 2011, 133,
6352–6363.
G. A. Molander, S. L. J. Trice, S. D. Dreher, J. Am. Chem. Soc.
2010, 132, 17701–17703.
C. Desmarets, R. Omar-Amrani, A. Walcarius, J. Lambert, B.
Champagne, Y. Fort, R. Schneider, Tetrahedron 2008, 64, 372–
381.
[24]
V. Papoian, T. Minehan, J. Org. Chem. 2008, 73, 7376–7379.
N. Marion, O. Navarro, J. Mei, E. D. Stevens, N. M. Scott, S. P. [25] K. Inamoto, C. Hasegawa, K. Hiroya, Y. Kondo, T. Osako, Y.
Nolan, J. Am. Chem. Soc. 2006, 128, 4101–4111; d) O. Navarro,
N. Marion, Y. Oonishi, R. A. Kelly, S. P. Nolan, J. Org. Chem.
2006, 71, 685–692; e) J. D. Blakemore, M. J. Chalkley, J. H.
Farnaby, L. M. Guard, N. Hazari, C. D. Incarvito, E. D. Luzik,
H. W. Suh, Organometallics 2011, 30, 1818–1829; f) S. C. Sau,
S. Santra, T. K. Sen, S. K. Mandal, D. Koley, Chem. Commun.
2012, 48, 555–557; g) T. Liu, X. Zhao, Q. Shen, L. Lu, Tetrahe-
dron 2012, 68, 6535–6547.
Uozumi, T. Doi, Chem. Commun. 2012, 48, 2912–2914.
[26] Y.-J. Kim, J.-H. Jung-Hyun Lee, T. Kim, J. Ham, Z. N. Zheng,
S. W. Lee, Eur. J. Inorg. Chem. 2012, 6011–6017.
[27] K. Mitsudo, S. Shimohara, J. Mizoguchi, H. Mandai, S. Suga,
Org. Lett. 2010, 12, 2702–2705.
[28] P. Gandeepan, K. Parthasarathy, C.-H. Cheng, J. Am. Chem.
Soc. 2010, 132, 8569–8571.
[29] S. M. Wong, C. M. So, K. H. Chung, C. P. Lau, F. Y. Kwong,
Eur. J. Org. Chem. 2012, 4172–4177.
[12] a) L. Botella, C. Najera, Angew. Chem. Int. Ed. 2002, 41, 179–
181; Angew. Chem. 2002, 114, 187–189; b) W. Susanto, C. Y. [30] Y.-Q. Tang, J.-M. Lu, L.-X. Shao, J. Organomet. Chem. 2011,
Chu, W. J. Ang, T. C. Chou, L. C. Lo, Y. Lam, Green Chem.
2012, 14, 77–80.
696, 3741–3744.
[31] H. Chen, Z. Huang, X. Hu, G. Tang, P. Xu, Y. Zhao, C.-H.
Cheng, J. Org. Chem. 2011, 76, 2338–2344.
[32] L. Ackermann, A.-R. Kapdi, S. Fenner, C. Kornhaas, C. Schul-
zke, Chem. Eur. J. 2011, 17, 2965–2971.
[13] a) T. Mino, Y. Shirae, M. Sakamoto, T. Fujita, J. Org. Chem.
2005, 70, 2191–2194; b) T. Mino, Y. Shirae, M. Sakamoto, T.
Fujita, Synlett 2003, 882–884.
[14] a) C. Xu, J.-F. Gong, T. Guo, Y.-H. Zhang, Y.-J. Wu, J. Mol.
Catal. A 2008, 279, 69–76; b) M. E. Hanhan, R. Martínez-
Máñez, J. V. Ros-Lis, Tetrahedron Lett. 2012, 53, 2388–2391; c)
W. Yang, C. Liu, J. Qiu, Chem. Commun. 2010, 46, 2659–2661;
d) D.-H. Lee, M.-J. Jin, Org. Lett. 2011, 13, 252–255.
[33] M.-G. Organ, S. Avola, I. Dubovyk, N. Hadei, E.-A.-B.
Kantchev, C.-J. O’Brien, C. Valente, Chem. Eur. J. 2006, 12,
4749–4755.
Received: February 21, 2014
Published Online: May 13, 2014
3916
www.eurjoc.org
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2014, 3909–3916