One-pot synthesis of symmetrical and unsymmetrical diarylmethanes via diborylmethane

Article abstract of DOI:10.1021/jo3015165

A one-pot synthesis of diarylmethanes from air-stable diborylmethane via the Suzuki-Miyaura cross-coupling reaction is described. The present approach realizes the synthesis of various symmetrical and unsymmetrical diarylmethanes in good to excellent yields.

Full text of DOI:10.1021/jo3015165

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One-Pot Synthesis of Symmetrical and Unsymmetrical
Diarylmethanes via Diborylmethane
Kohei Endo,*,†,‡ Takafumi Ishioka,§ Takahiro Ohkubo,§ and Takanori Shibata*,§
†Division of Material Sciences, Graduate School of Natural Science and Technology, Kanazawa University, Kakuma, Kanazawa
920-1192, Japan
‡PRESTO, Japan Science and Technology Agency (JST), 4-1-8 Honcho Kawaguchi, Saitama, 332-0012, Japan
§Department of Chemistry and Biochemistry, School of Advanced Science and Engineering, Waseda University, Shinjuku, Tokyo,
169-8555, Japan
S
* Supporting Information
ABSTRACT: A one-pot synthesis of diarylmethanes from air-stable
diborylmethane via the Suzuki−Miyaura cross-coupling reaction is
described. The present approach realizes the synthesis of various
symmetrical and unsymmetrical diarylmethanes in good to excellent yields.
halides is needed for the preparation of unsymmetrical
diarylmethanes in synthetic organic chemistry.
INTRODUCTION
■
Diarylmethanes are an important class of molecules in
medicinal chemistry.1 Although the one-pot synthesis of
diarylmethanes is an indispensable approach, the incorporation
of desired aryl units into a methylene unit for the synthesis of
unsymmetrical diarylmethanes in a single reaction vessel is
difficult to achieve. The typical procedure for the synthesis of
diarylmethanes is the cross-coupling reaction of benzyl halides
with aryl nucleophiles or aryl halides with benzylic nucleophiles
(Scheme 1).2 The stepwise cross-coupling of silylmethylstan-
RESULTS AND DISCUSSION
■
We previously reported the use of air-stable diborylmethane
derivatives for the regiospecific and chemoselective Suzuki−
Miyaura cross-coupling reaction (SMC) at room temperature.4
The reaction proceeds under ambient conditions and gives
benzylboronate derivatives without a subsequent cross-coupling
reaction into diarylmethanes. Since various examinations of the
SMC showed that alkylboronic acid pinacol esters were not
suitable organoboron compounds for achieving a high yield due
to the slow generation of a borate intermediate, even in the
presence of a strong or specific base such as TlOH, there is only
one example of the use of B-benzyl-9-borabicyclo-[3.3.1]-
nonane derivatives as organoboron compounds for the efficient
synthesis of diarylmethanes.5 Benzyl boronic acid pinacol esters
bearing β-C−H bonds have recently been reported to give the
products in moderate yields in the presence of a relatively large
amount of catalyst, ligands, and a stoichiometric amount of
Ag2O as a base.6 In this context, we embarked on our strategy
for the use of diborylmethane 1 as a methylene unit (Table 1).
Although the SMC of diborylmethane 1 (1 equiv) and 1-
bromo-4-methylbenzene (2a) (2.2 equiv) in the presence of
Pd[P(t-Bu)3]2 (10 mol %) and KOH (2 equiv) at room
temperature gave the benzylboronate 3a in good yield, the
desired diarylmethane 4a was not obtained at all. In contrast,
subsequent heating at 60 °C in the second coupling step gave
the desired product 4a in low yield, and a considerable amount
of benzylboronate 3a remained. When we added KOH (3
equiv) after we confirmed the consumption of diborylmethane
1, the second coupling reaction took place smoothly at 60 °C
Scheme 1. Concept of One-Pot Synthesis of Diarylmethanes
nane with arylhalides reported by Itami et al. is an advanced
approach to the synthesis of unsymmetrical diarylmethanes.3
These procedures require the preparation of the corresponding
benzyl halides and benzyl nucleophiles as intermediates at each
step. Therefore, a one-pot approach starting from stable
dimetallomethane derivatives with commercially available aryl
Received: July 18, 2012
© XXXX American Chemical Society
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Table 1. Conditions for Symmetrical Diarylmethanes
Table 2. Synthesis of Symmetrical Diarylmethanes
a
entry
additive
none
temp (°C) time x, y (h)
yield (%)
1
2
3
rt
5, 24
5, 14
5, 15
5, 12
10, −
3a, 80; 4a, −
3a, 76; 4a, 14
3a, −; 4a, 91
3a, −; 4a, >98
3a, −; 4a, 59
none
60
60
60
60
KOH (3 equiv)
KOH (3 equiv)
b
4
c
5
none
a
b
NMR yields. KOH (1.5 equiv) was used at the initial coupling
reaction. The reaction of 1 and 2a was carried out in the presence of
c
KOH (5 equiv) at 60 °C for 10 h from the beginning of the reaction.
and gave the desired product 4a in high yield (entry 3). The use
of KOH (1.5 equiv) at the initial coupling improved the yield of
product 4a (entry 4). The first reaction temperature was
important; the reaction at 60 °C from the beginning of the
reaction in the presence of KOH (5 equiv) diminished the yield
of product 4a with the decomposition of 1 and 3a; proto-
deboronation proceeded (entry 5).
A wide variety of aryl halides could participate in the reaction
to give symmetrical diarylmethanes under the optimized
conditions. The reaction of diborylmethane 1 and arylbromides
2a−k was carried out in the presence of Pd[P(t-Bu)3]2 (5 mol
%) and KOH (1.5 equiv) at room temperature; after the first
coupling reaction, KOH (3 equiv) was added and the reaction
mixture was heated at 60 °C (Table 2). We obtained
diarylmethanes derived from aryl bromides 2a−e bearing an
electron-donating or -withdrawing substituent at the 4-position
(entries 1−5).7 Aryl bromides 2f and 2g bearing a substituent
at the 3-position participated in the reaction to give the
corresponding products 4f and 4g, which are typically difficult
to synthesize regioselectively via the conventional Friedel−
Crafts approach (entries 6 and 7). The sterically hindered
ortho-substituted diarylmethanes 4h−j could be obtained
(entries 8−10). Furthermore, bulky disubstituted aryl bromides
2k gave the desired product 4k in moderate yield (entry 11).
Modification of the reaction conditions for the synthesis of
unsymmetrical diarylmethanes was explored (Scheme 2). The
complete consumption of diborylmethane 1 or Ar1Br at the first
coupling is important for decreasing side-products; remaining 1
would lead to the generation of 4-Ar12 and 4-Ar22 at the second
coupling reaction. We initially focused on the amount of KOH
to complete the first coupling reaction of diborylmethane 1 (1
equiv) with 1-bromo-4-methylbenzene (2a) (1 equiv) (Table
3). The reaction of 1 and 2a was conducted in the presence of
Pd[P(t-Bu)3]2 (10 mol %) and KOH in dioxane at room
temperature. The amount of KOH is critical, and the optimum
conditions gave 3a in high yield when KOH (2 equiv) was used
(entry 3).
a
The reaction of 1 (0.2 mmol), aryl bromide 2 (0.44 mmol), KOH
(0.3 mmol, 8 N aq), Pd[P(t-Bu)3]2 (0.01 mmol, 5 mol %) was carried
out in dioxane (2 mL). After 12 h stirring at room temperature, KOH
(0.6 mmol, 8 N aq) was added. Then the reaction mixture was stirred
at 60 °C. The yield of the reaction in larger scale using 1 (1 mmol)
and 2a (2.2 mmol) was described in parentheses.
b
Scheme 2. Possible Products of One-Pot Synthesis of
Diarylmethanes
We examined the one-pot synthesis of unsymmetrical
diarylmethane derivatives (Table 4). After the first coupling
reaction of diborylmethane 1 and 1-bromo-4-methylbenzene
(2a), as shown in entry 3 of Table 3, 1-bromo-4-
methoxybenzene (2c) (2 equiv) and KOH (3 equiv) were
added. However, the reaction gave the desired product 5a in
moderate yield along with symmetrical diarylmethanes 4a and
4c (entry 1). Further examination of the reaction conditions
showed that the use of diborylmethane 1 (2 equiv) and 1-
bromo-4-methylbenzene (2a) (1 equiv) at the first coupling
reaction, 1-bromo-4-methoxybenzene (2c) (4 equiv) in the
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Representative results with other combinations of arylbro-
mides are shown in Table 6. The reaction of diborylmethane 1,
1-bromo-4-methylbenzene (2a), and 1-bromo-4-
(trifluoromethyl)benzene (2m) or 3-bromothiophene (2s)
gave the desired product 5q or 5r in respective yields of 88
or 82% (entries 1 and 2). The reaction of diborylmethane 1, 1-
bromo-4-fluorobenzene (2d), and 1-bromo-4-
(trifluoromethyl)benzene (2m) gave the desired product 5s
in 77% yield (entry 3). Sterically hindered aryl bromides gave
the products in reduced yields; the representative results using
1-bromo-2-methoxybenzene (2i) and 1-bromo-2-methylben-
zene (2h) gave the desired product 5t in 44% yield (entry 4).
We next examined the one-pot cross-coupling of diboryl-
methane 1 with an aryl bromide and benzyl bromide or
cinnamyl halides. The reaction of diborylmethane 1 and benzyl
bromide (6a), cinnamyl bromide (6b), or cinnamyl chloride
(6c) was carried out under the same reaction conditions as for
diarylmethane derivatives (Scheme 3). We previously reported
that the cross-coupling reaction between diborylmethane 1 and
benzyl bromide or allyl bromide derivatives proceeded
efficiently.4 The reaction of 1, 2c, and benzyl bromide (6a)
gave the desired product 7a in 67% yield. The reaction of 1, 2c,
and cinnamyl bromide (6b) or cinnamyl chloride (6c)
proceeded to give the corresponding product 7b in 47 or
66% yield. The unreacted 6b or 6c was recovered after 24 h.
In conclusion, we achieved the one-pot synthesis of various
diarylmethane derivatives via the Suzuki−Miyaura cross-
coupling reaction of diborylmethane derivative. The reaction
can be controlled by adjusting the reaction temperature and the
amount of base. The synthesis of unsymmetrical diaryl-
methanes required the use of 2 equiv of diborylmethane 1
for complete consumption of the first arylbromides, and excess
base in the second coupling reaction to negate the excess
diborylmethane 1; a trace amount of symmetrical diaryl-
methanes were generated from the second arylbromides. The
present one-pot procedure is a convenient approach to the
synthesis of densely functionalized diarylmethanes, which are
useful compounds in organic synthesis.
Table 3. Preliminary Screening of Conditions for First
Coupling
a
entry
x
yield (%)
1
2
3
4
1.0
1.5
2.0
2.5
36
78
92
57
a
NMR yields.
Table 4. Conditions for Unsymmetrical Diarylmethanes
a
entry
Ar1Br
Ar2Br
x
y
m
n
yield (%)
1
2
3
4
5
6
2a
2c
1
2
2
2
2
2
2
2
2
2
2
2
2
4
4
4
4
3
3
5
4
5
6
6
71
84
88
92
94
94
2c
2a
a
NMR yields.
presence of additional KOH (5 equiv) at the second coupling
reaction gave the product 5a in high yield (entry 2). The excess
amount of KOH in the second coupling reaction could destroy
diborylmethane 1; thus, the further coupling reaction of 1 with
2c did not proceed.4 When 1-bromo-4-methoxybenzene (2c)
for the first coupling reaction and 1-bromo-4-methylbenzene
(2a) for the second coupling reaction were used, the desired
product 5a was obtained in an improved yield of 88% (entry 3).
After we examined the amount of base and 2a, we decided to
use the optimum conditions for the further screening of aryl
bromides (entries 4−6).
We examined the sequential one-pot coupling reaction of
various aryl halides under the optimum reaction conditions
(Table 5). The coupling reactions using 1-bromo-4-methox-
ybenzene (2c) and 4-substituted aryl bromides gave the desired
products 5a−e in moderate to excellent yields (entries 1−5).
Notably, the electron-withdrawing group can be tolerated in the
second coupling reaction. Other substituted aryl bromides
bearing sterically hindered substituents gave the desired
products 5f−k in good yields (entries 6−11). Heteroaryl
bromides are suitable reactants: 2-bromothiophene (2r), 3-
bromothiophene (2s), 3-bromofuran (2t), 2-bromopyridine
(2u), and 3-bromopyridine (2v) were good coupling partners.
There were no considerable byproducts; decomposition of the
benzylboronate intermediate during the reaction decreased the
yield of products when less-reactive aryl bromides were used in
the second coupling reaction.
EXPERIMENTAL SECTION
■
Synthesis of Di-p-tolylmethane (4a).8 To a solution of
diborylmethane 1 (53.6 mg, 0.200 mmol), 1-bromo-4-methylbenzene
(2a) (76.4 mg, 0.44 mmol, 2.2 equiv), and Pd[P(t-Bu)3]2 (5.1 mg, 10
μmol, 5 mol %) in dioxane (2.0 mL) was added 8 N KOH aq (36 μL,
0.3 mmol, 1.5 equiv) at room temperature. After 12 h stirring at room
temperature, 8 N KOH aq (72 μL, 0.6 mmol, 3 equiv) was added. The
mixture was stirred at 60 °C for 12 h and passed through a pad of silica
gel with ether. Concentration gave the residue, the NMR yield of
which was determined to be >98% by the integration ratio of the crude
NMR with 1,1,2,2-tetrachloroethane as an internal standard.
Purification by silica gel column chromatography (hexane) gave the
product 4a in 0.174 mmol, 89% yield (34.8 mg/39.3 mg); the reaction
using 1 (0.98 mmol) and 2a (2.34 mmol) gave the product 4a in 0.809
mmol, 82% yield (158.7 mg/193.8 mg).
Synthesis of Diphenylmethane (4b).9 To a solution of
diborylmethane 1 (52.8 mg, 0.197 mmol), p-bromobenzene (2b)
(68.5 mg, 0.44 mmol, 2.2 equiv), and Pd[P(t-Bu)3]2 (5.1 mg, 10 μmol,
5 mol %) in dioxane (2.0 mL) was added 8 N KOH aq (36 μL, 0.3
mmol, 1.5 equiv) at room temperature. After 12 h stirring at room
temperature, 8 N KOH aq (71 μL, 0.6 mmol, 3 equiv) was added. The
mixture was stirred at 60 °C for 4 h and passed through a pad of silica
gel with ether. Concentration gave the residue, the NMR yield of
which was determined to be 77% by the integration ratio of the crude
NMR with 1,1,2,2-tetrachloroethane as an internal standard.
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Table 5. Synthesis of Unsymmetrical Diarylmethanes
a
The reaction of 1 (0.4 mmol), aryl bromide 2 (0.2 mmol), KOH (0.4 mmol, 8 N aq), Pd[P(t-Bu)3]2 (0.02 mmol, 10 mol %) was carried out in
dioxane (2 mL). After 3 h stirring at room temperature, another 2 (0.6 mmol) and KOH (1.2 mmol, 8 N aq) were added. Then the reaction mixture
b
was stirred at 60 °C. The yield of the reaction in larger scale using 1 (2 mmol), 2c (1 mmol), and 2a (3 mmol) was described in parentheses.
Purification by silica gel column chromatography (hexane) gave the
product 4b in 0.130 mmol, 66% yield (21.8 mg/33.1 mg).
integration ratio of the crude NMR with 1,1,2,2-tetrachloroethane as
an internal standard. Purification by silica gel column chromatography
(hexane/ether = 30/1) gave the product 4d in 0.171 mmol, 87% yield
(38.9 mg/44.9 mg).
Synthesis of Bis(4-methoxyphenyl)methane (4c).10 To a
solution of diborylmethane 1 (52.7 mg, 0.197 mmol), 1-bromo-4-
methoxybenzene (2c) (82.1 mg, 0.44 mmol, 2.2 equiv), and Pd[P(t-
Bu)3]2 (5.1 mg, 10 μmol, 5 mol %) in dioxane (2.0 mL) was added 8
N KOH aq (36 μL, 0.3 mmol, 1.5 equiv) at room temperature. After
12 h stirring at room temperature, 8 N KOH aq (72 μL, 0.6 mmol, 3
equiv) was added. The mixture was stirred at 60 °C for 5 h and passed
through a pad of silica gel with ether. Concentration gave the residue,
the NMR yield of which was determined to be >98% by the
Synthesis of Bis(4-fluorophenyl)methane (4d).11 To a
solution of diborylmethane 1 (53.6 mg, 0.200 mmol), 1-bromo-4-
fluorobenzene (2d) (74.8 mg, 0.43 mmol, 2.2 equiv), and Pd[P(t-
Bu)3]2 (5.1 mg, 10 μmol, 5 mol %) in dioxane (2.0 mL) was added 8
N KOH aq (36 μL, 0.3 mmol, 1.5 equiv) at room temperature. After
12 h stirring at room temperature, 8 N KOH aq (72 μL, 0.6 mmol, 3
equiv) was added. The mixture was stirred at 60 °C for 6.5 h and
D
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product 4e in 0.107 mmol, 54% yield (25.3 mg/47.0 mg); white solid:
Table 6. Other Combination of Aryl bromides
1
mp 50 °C; H NMR (CDCl3, 400 MHz) δ 7.28−7.23 (m, 4H), 7.08
(m, 4H), 3.91 (s, 2H); 13C NMR (CDCl3, 125 MHz) δ 139.1, 132.2,
130.3, 128.8, 40.6; IR (neat, cm−1) 3031, 2923, 2858, 1091, 806;
HRMS (FAB, positive) m/z calcd for C13H10Cl2 236.0160, found
236.0157.
Synthesis of Di-m-tolylmethane (4f). To a solution of
diborylmethane 1 (53.6 mg, 0.200 mmol), 1-bromo-3-methylbenzene
(2f) (74.8 mg, 0.44 mmol, 2.2 equiv), and Pd[P(t-Bu)3]2 (5.2 mg, 10
μmol, 5 mol %) in dioxane (2.0 mL) was added 8 N KOH aq (36 μL,
0.3 mmol, 1.5 equiv) at room temperature. After 12 h stirring at room
temperature, 8 N KOH aq (72 μL, 0.6 mmol, 3 equiv) was added. The
mixture was stirred at 60 °C for 5 h and passed through a pad of silica
gel with ether. Concentration gave the residue, the NMR yield of
which was determined to be 74% by the integration ratio of the crude
NMR with 1,1,2,2-tetrachloroethane as an internal standard.
Purification by silica gel column chromatography (hexane) gave the
product 4f in 0.141 mmol, 70% yield (27.6 mg/39.3 mg); yellow oil:
1H NMR (CDCl3, 400 MHz) δ 7.17 (m, 2H), 7.02−6.95 (m, 6H),
3.90 (s, 2H), 2.31 (s, 6H); 13C NMR (CDCl3, 125 MHz) δ 141.3,
138.1, 129.8, 128.4, 126.9, 126.1, 42.0, 21.5; IR (neat, cm−1) 3021,
2922, 2863, 1459, 1377, 771, 693; HRMS (FAB, positive) m/z calcd
for C15H16 196.1252, found 196.1244.
Synthesis of Bis(3-methoxyphenyl)methane (4g).12 To a
solution of diborylmethane 1 (54.2 mg, 0.202 mmol), 1-bromo-3-
methoxybenzene (2g) (81.3 mg, 0.43 mmol, 2.2 equiv), and Pd[P(t-
Bu)3]2 (5.1 mg, 10 μmol, 5 mol %) in dioxane (2.0 mL) was added 8
N KOH aq (36 μL, 0.3 mmol, 1.5 equiv) at room temperature. After
12 h stirring at room temperature, 8 N KOH aq (73 μL, 0.6 mmol, 3
equiv) was added. The mixture was stirred at 60 °C for 4 h and passed
through a pad of silica gel with ether. Concentration gave the residue,
the NMR yield of which was determined to be 71% by the integration
ratio of the crude NMR with 1,1,2,2-tetrachloroethane as an internal
standard. Purification by silica gel column chromatography (hexane/
ether = 30/1) gave the product 4g in 0.131 mmol, 65% yield (30.0
mg/46.2 mg): NMR chemical shifts were literature known; IR (neat,
cm−1) 3006, 2937, 2835, 1260, 774, 692; HRMS (FAB, positive) m/z
calcd for C15H16O2 228.1150, found 228.1148.
a
The reaction of 1 (0.4 mmol), aryl bromide 2 (0.2 mmol), KOH (0.4
mmol, 8 N aq), Pd[P(t-Bu)3]2 (0.02 mmol, 10 mol %) was carried out
in dioxane (2 mL). After 3 h stirring at room temperature, another 2
(0.6 mmol) and KOH (1.2 mmol, 8 N aq) were added. Then the
reaction mixture was stirred at 60 °C.
Scheme 3. Benzylation and Allylation
Synthesis of Di-o-tolylmethane (4h).13 To a solution of
diborylmethane 1 (53.4 mg, 0.199 mmol), 1-bromo-2-methylbenzene
(2h) (74.5 mg, 0.44 mmol, 2.2 equiv), and Pd[P(t-Bu)3]2 (5.1 mg, 10
μmol, 5 mol %) in dioxane (2.0 mL) was added 8 N KOH aq (36 μL,
0.3 mmol, 1.5 equiv) at room temperature. After 12 h stirring at room
temperature, 8 N KOH aq (72 μL, 0.6 mmol, 3 equiv) was added. The
mixture was stirred at 60 °C for 2 h and passed through a pad of silica
gel with ether. Concentration gave the residue, the NMR yield of
which was determined to be 63% by the integration ratio of the crude
NMR with 1,1,2,2-tetrachloroethane as an internal standard.
Purification by silica gel column chromatography (hexane) gave the
product 4h in 0.109 mmol, 55% yield (21.4 mg/39.1 mg).
Synthesis of Bis(2-methoxyphenyl)methane (4i).12 To a
solution of diborylmethane 1 (52.5 mg, 0.196 mmol), 1-bromo-2-
methoxybenzene (2i) (81.5 mg, 0.44 mmol, 2.2 equiv), and Pd[P(t-
Bu)3]2 (5.1 mg, 10 μmol, 5 mol %) in dioxane (2.0 mL) was added 8
N KOH aq (35 μL, 0.3 mmol, 1.5 equiv) at room temperature. After
12 h stirring at room temperature, 8 N KOH aq (71 μL, 0.6 mmol, 3
equiv) was added. The mixture was stirred at 60 °C for 3 h and passed
through a pad of silica gel with ether. Concentration gave the residue,
the NMR yield of which was determined to be 50% by the integration
ratio of the crude NMR with 1,1,2,2-tetrachloroethane as an internal
standard. Purification by silica gel column chromatography (hexane/
ether = 30/1) gave the product 4i in 0.0898 mmol, 46% yield (20.5
mg/44.7 mg): NMR chemical shifts were literature known; IR (neat,
cm−1) 3066, 3026, 2838, 1458, 1244, 751; HRMS (FAB, positive) m/z
calcd for C15H16O2 228.1150, found 228.1157.
passed through a pad of silica gel with ether. Concentration gave the
residue, the NMR yield of which was determined to be 86% by the
integration ratio of the crude NMR with 1,1,2,2-tetrachloroethane as
an internal standard. Purification by silica gel column chromatography
(hexane) gave the product 4d in 0.155 mmol, 78% yield (31.7 mg/
1
40.8 mg): H, 13C NMR chemical shifts, and HRMS were literature
known; 19F NMR (CDCl3, 466 MHz) δ −117.0; IR (neat, cm−1)
3041, 2925, 1507, 1224, 819.
Synthesis of Bis(4-chlorophenyl)methane (4e). To a solution
of diborylmethane 1 (53.1 mg, 0.198 mmol), 1-bromo-4-chloroben-
zene (2e) (84.2 mg, 0.44 mmol, 2.2 equiv), and Pd[P(t-Bu)3]2 (5.2
mg, 10 μmol, 5 mol %) in dioxane (2.0 mL) was added 8 N KOH aq
(36 μL, 0.3 mmol, 1.5 equiv) at room temperature. After 12 h stirring
at room temperature, 8 N KOH aq (72 μL, 0.6 mmol, 3 equiv) was
added. The mixture was stirred at 60 °C for 2 h and passed through a
pad of silica gel with ether. Concentration gave the residue, the NMR
yield of which was determined to be 65% by the integration ratio of
the crude NMR with 1,1,2,2-tetrachloroethane as an internal standard.
Purification by silica gel column chromatography (hexane) gave the
Synthesis of Bis(2-isopropylphenyl)methane (4j). To a
solution of diborylmethane 1 (51.7 mg, 0.193 mmol), 1-bromo-2-
isopropylbenzene (2j) (86.1 mg, 0.43 mmol, 2.2 equiv), and Pd[P(t-
Bu)3]2 (5.1 mg, 10 μmol, 5 mol %) in dioxane (2.0 mL) was added 8
N KOH aq (35 μL, 0.3 mmol, 1.5 equiv) at room temperature. After
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12 h stirring at room temperature, 8 N KOH aq (70 μL, 0.6 mmol, 3
equiv) was added. The mixture was stirred at 60 °C for 2.5 h and
passed through a pad of silica gel with ether. Concentration gave the
residue, the NMR yield of which was determined to be 49% by the
integration ratio of the crude NMR with 1,1,2,2-tetrachloroethane as
an internal standard. Purification by silica gel column chromatography
(hexane) gave the product 4j in 0.0792 mmol, 41% yield (20.0 mg/
shifts were literature known; 19F NMR (CDCl3, 466 MHz) δ −62.2;
IR (neat, cm−1) 2934, 2838, 1248, 1123, 1037, 814; HRMS (FAB,
positive) m/z calcd for C15H13F3O 266.0918, found 266.0916.
Synthesis of 1-Methoxy-4-(4-nitrobenzyl)benzene (5d). To a
solution of diborylmethane 1 (105.5 mg, 0.39 mmol, 2 equiv), 1-
bromo-4-methoxybenzene (2c) (36.8 mg, 0.197 mmol), and Pd[P(t-
Bu)3]2 (10.3 mg, 20 μmol, 10 mol %) in dioxane (2.0 mL) was added
8 N KOH aq (47 μL, 0.4 mmol, 2 equiv) at room temperature. After 3
h stirring at room temperature, 8 N KOH aq (142 μL, 1.2 mmol, 6
equiv) and 1-bromo-4-nitrobenzene (2n) (119.1 mg, 0.59 mmol, 3
equiv) were added. The mixture was stirred at 60 °C for 16 h and
passed through a pad of silica gel with ether. Purification by silica gel
column chromatography (hexane/ether = 10/1) gave the product 5d
1
48.7 mg); yellow oil: H NMR (CDCl3, 400 MHz) δ 7.34−7.30 (m,
2H), 7.25−7.20 (m, 2H), 7.10−7.05 (m, 2H), 6.88−6.84 (m, 2H),
4.08 (s, 2H), 3.13 (sept, J = 6.8 Hz, 2H), 1.21 (d, J = 6.8 Hz, 12H);
13C NMR (CDCl3, 125 MHz) δ 147.0, 137.5, 129.8, 126.7, 125.8,
125.2, 35.3, 29.0, 23.7; IR (neat, cm−1) 3026, 2961, 2873, 1382, 1035,
758; HRMS (FAB, positive) m/z calcd for C19H24 252.1878, found
252.1883.
1
in 0.148 mmol, 75% yield (36.0 mg/47.9 mg); orange oil: H NMR
(CDCl3, 400 MHz) δ 8.14 (d, J = 8.4 Hz, 2H), 7.34−7.31 (m, 2H),
7.09 (d, J = 8.4 Hz, 2H), 6.86 (d, J = 8.4 Hz, 2H), 4.02 (s, 2H), 3.80
(s, 3H); 13C NMR (CDCl3, 125 MHz) δ 158.5, 149.5, 146.5, 131.3,
130.0, 129.6, 123.8, 114.3, 55.4, 41.0; IR (neat, cm−1) 2954, 2930,
2837, 1250, 859, 828; HRMS (FAB, positive) m/z calcd for
C14H13NO3 243.0895, found 243.0907.
Synthesis of Bis(2,6-dimethylphenyl)methane (4k). To a
solution of diborylmethane 1 (54.4 mg, 0.203 mmol), 2-bromo-1,3-
dimethylbenzene (2k) (78.3 mg, 0.42 mmol, 2.2 equiv), and Pd[P(t-
Bu)3]2 (5.1 mg, 10 μmol, 5 mol %) in dioxane (2.0 mL) was added 8
N KOH aq (36 μL, 0.3 mmol, 1.5 equiv) at room temperature. After
12 h stirring at room temperature, 8 N KOH aq (72 μL, 0.6 mmol, 3
equiv) was added. The mixture was stirred at 60 °C for 4.5 h and
passed through a pad of silica gel with ether. Concentration gave the
residue, the NMR yield of which was determined to be 61% by the
integration ratio of the crude NMR with 1,1,2,2-tetrachloroethane as
an internal standard. Purification by silica gel column chromatography
(hexane) gave the product 4k in 0.118 mmol, 58% yield (26.4 mg/45.5
Synthesis of Ethyl 4-(4-methoxybenzyl)benzoate (5e). To a
solution of diborylmethane 1 (107.4 mg, 0.40 mmol, 2 equiv), 1-
bromo-4-methoxybenzene (2c) (37.4 mg, 0.200 mmol), and Pd[P(t-
Bu)3]2 (10.3 mg, 20 μmol, 10 mol %) in dioxane (2.0 mL) was added
8 N KOH aq (48 μL, 0.4 mmol, 2 equiv) at room temperature. After 3
h stirring at room temperature, 8 N KOH aq (144 μL, 1.2 mmol, 6
equiv) and ethyl 4-bromobenzoate (2o) (138.8 mg, 0.61 mmol, 3
equiv) were added. The mixture was stirred at 60 °C for 24 h and
passed through a pad of silica gel with ether. Purification by silica gel
column chromatography (hexane/ether = 30/1) gave the product 5e
in 0.0858 mmol, 43% yield (23.2 mg/54.1 mg); yellow solid: mp 42
°C; 1H NMR (CDCl3, 400 MHz) δ 7.96 (d, J = 8.0 Hz, 2H), 7.24 (d, J
= 8.0 Hz, 2H), 7.09 (d, J = 8.4 Hz, 2H), 6.83 (d, J = 8.4 Hz, 2H), 4.36
(q, J = 7.2 Hz, 2H), 3.97 (s, 2H), 3.78 (s, 3H), 1.38 (t, J = 7.2 Hz,
3H); 13C NMR (CDCl3, 125 MHz) δ 166.7, 158.2, 147.0, 132.4,
130.0, 129.9, 128.9, 128.4, 114.1, 60.9, 55.4, 44.1, 14.4; IR (neat, cm−1)
2932, 2836, 1719, 1247, 1034, 801, 668; HRMS (ESI, positive) m/z
calcd for C17H18NaO3 [M + Na]+ 293.1154, found 293.1142.
1
mg); white solid: mp 93 °C; H NMR (CDCl3, 400 MHz) δ 7.04−
6.93 (m, 6H), 4.01 (s, 2H), 2.12 (s, 12H); 13C NMR (CDCl3, 125
MHz) δ 137.9, 136.9, 128.7, 125.8, 31.9, 21.0; IR (neat, cm−1) 3061,
3026, 2924, 2852, 768; HRMS (FAB, positive) m/z calcd for C17H20
224.1565, found 224.1564.
Synthesis of 1-Methoxy-4-(4-methylbenzyl)benzene (5a).14
To a solution of diborylmethane 1 (111.3 mg, 0.42 mmol, 2 equiv), 1-
bromo-4-methoxybenzene (2c) (38.2 mg, 0.204 mmol), and Pd[P(t-
Bu)3]2 (10.2 mg, 20 μmol, 10 mol %) in dioxane (2.0 mL) was added
8 N KOH aq (49 μL, 0.4 mmol, 2 equiv) at room temperature. After 3
h stirring at room temperature, 8 N KOH aq (147 μL, 1.2 mmol, 6
equiv) and 1-bromo-4-methylbenzene (2a) (106.7 mg, 0.62 mmol, 3
equiv) were added. The mixture was stirred at 60 °C for 16 h and
passed through a pad of silica gel with ether. Purification by silica gel
column chromatography (hexane/ether = 30/1) gave the product 5a
in 0.192 mmol, 94% yield (40.8 mg/43.4 mg); the reaction using 1
(531.7 mg, 2.0 mmol, 2 equiv), 2c (186.2 mg, 1 mmol), and 2a (510.8
mg, 3.0 mmol, 3 equiv) gave the product 5a in 0.866 mmol, 87% yield
(183.8 mg/211.3 mg).
Synthesis of 1-Methoxy-4-(3-methylbenzyl)benzene (5f).16
To a solution of diborylmethane 1 (105.2 mg, 0.39 mmol, 2 equiv), 1-
bromo-4-methoxybenzene (2c) (36.7 mg, 0.196 mmol), and Pd[P(t-
Bu)3]2 (10.1 mg, 20 μmol, 10 mol %) in dioxane (2.0 mL) was added
8 N KOH aq (47 μL, 0.4 mmol, 2 equiv) at room temperature. After 3
h stirring at room temperature, 8 N KOH aq (141 μL, 1.2 mmol, 6
equiv) and 1-bromo-3-methylbenzene (2f) (100.8 mg, 0.59 mmol, 3
equiv) were added. The mixture was stirred at 60 °C for 16 h and
passed through a pad of silica gel with ether. Purification by silica gel
column chromatography (hexane/ether = 30/1) gave the product 5f in
Synthesis of 1-(4-Fluorobenzyl)-4-methoxybenzene (5b).10
To a solution of diborylmethane 1 (106.3 mg, 0.40 mmol, 2 equiv), 1-
bromo-4-methoxybenzene (2c) (37.2 mg, 0.199 mmol), and Pd[P(t-
Bu)3]2 (10.3 mg, 20 μmol, 10 mol %) in dioxane (2.0 mL) was added
8 N KOH aq (48 μL, 0.4 mmol, 2 equiv) at room temperature. After 3
h stirring at room temperature, 8 N KOH aq (143 μL, 1.2 mmol, 6
equiv) and 1-bromo-4-fluorobenzene (2d) (103.0 mg, 0.59 mmol, 3
equiv) were added. The mixture was stirred at 60 °C for 16 h and
passed through a pad of silica gel with ether. Purification by silica gel
column chromatography (hexane/ether = 30/1) gave the product 5b
in 0.182 mmol, 91% yield (39.3 mg/43.0 mg): 1H, 13C NMR chemical
shifts, IR, and HRMS were literature known; 19F NMR (CDCl3, 466
MHz) δ −117.4.
1
0.185 mmol, 94% yield (39.2 mg/41.7 mg): H NMR chemical shifts
are literature known; 13C NMR (CDCl3, 125 MHz) δ 158.0, 141.6,
138.1, 133.5, 129.9, 129.7, 128.4, 126.8, 125.9, 113.9, 53.3, 41.1, 21.5;
IR (neat, cm−1) 3006, 2912, 2834, 1464, 1248, 819, 788, 695; HRMS
(FAB, positive) m/z calcd for C15H16O 212.1201, found 212.1210.
Synthesis of 1-Methoxy-4-(2-methylbenzyl)benzene (5g).17
To a solution of diborylmethane 1 (105.2 mg, 0.39 mmol, 2 equiv), 1-
bromo-4-methoxybenzene (2c) (36.8 mg, 0.197 mmol), and Pd[P(t-
Bu)3]2 (10.3 mg, 20 μmol, 10 mol %) in dioxane (2.0 mL) was added
8 N KOH aq (47 μL, 0.4 mmol, 2 equiv) at room temperature. After 3
h stirring at room temperature, 8 N KOH aq (142 μL, 1.2 mmol, 6
equiv) and 1-bromo-2-methylbenzene (2h) (100.1 mg, 0.59 mmol, 3
equiv) were added. The mixture was stirred at 60 °C for 16 h and
passed through a pad of silica gel with ether. Purification by silica gel
column chromatography (hexane/ether = 30/1) gave the product 5g
Synthesis of 1-(4-Methoxybenzyl)-4-(trifluoromethyl)-
benzene (5c).15 To a solution of diborylmethane 1 (106.3 mg,
0.40 mmol, 2 equiv), 1-bromo-4-methoxybenzene (2c) (37.1 mg,
0.198 mmol), and Pd[P(t-Bu)3]2 (10.2 mg, 20 μmol, 10 mol %) in
dioxane (2.0 mL) was added 8 N KOH aq (48 μL, 0.4 mmol, 2 equiv)
at room temperature. After 3 h stirring at room temperature, 8 N
KOH aq (143 μL, 1.2 mmol, 6 equiv) and 1-bromo-4-
(trifluoromethyl)benzene (2m) (132.2 mg, 0.59 mmol, 3 equiv)
were added. The mixture was stirred at 60 °C for 16 h and passed
through a pad of silica gel with ether. Purification by silica gel column
chromatography (hexane/ether = 30/1) gave the product 5c in 0.159
1
in 0.163 mmol, 83% yield (34.5 mg/41.8 mg): H and 13C NMR
chemical shifts were literature known; IR (neat, cm−1) 3010, 2953,
2838, 1247, 1037, 812, 747; HRMS (FAB, positive) m/z calcd for
C15H16O 212.1201, found 212.1194.
Synthesis of 1-(2-Isopropylbenzyl)-4-methoxybenzene (5h).
To a solution of diborylmethane 1 (108.4 mg, 0.40 mmol, 2 equiv), 1-
bromo-4-methoxybenzene (2c) (38.3 mg, 0.205 mmol), and Pd[P(t-
1
mmol, 80% yield (42.3 mg/52.8 mg): H and 13C NMR chemical
F
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Featured Article
Bu)3]2 (10.2 mg, 20 μmol, 10 mol %) in dioxane (2.0 mL) was added
8 N KOH aq (49 μL, 0.4 mmol, 2 equiv) at room temperature. After 3
h stirring at room temperature, 8 N KOH aq (147 μL, 1.2 mmol, 6
equiv) and 1-bromo-2-isopropylbenzene (2j) (121.1 mg, 0.61 mmol, 3
equiv) were added. The mixture was stirred at 60 °C for 16 h and
passed through a pad of silica gel with ether. Purification by silica gel
column chromatography (hexane/ether = 30/1) gave the product 5h
h stirring at room temperature, 8 N KOH aq (142 μL, 1.2 mmol, 6
equiv) and 2-bromothiophene (2r) (97.1 mg, 0.60 mmol, 3 equiv)
were added. The mixture was stirred at 60 °C for 16 h and passed
through a pad of silica gel with ether. Purification by silica gel column
chromatography (hexane/ether = 30/1) gave the product 5l in 0.164
1
mmol, 83% yield (33.6 mg/40.4 mg); yellow oil: H and 13C NMR
chemical shifts were literature known; IR (neat, cm−1) 2908, 2834,
1248, 1037, 851, 818; HRMS (FAB, positive) m/z calcd for C12H12OS
204.0609, found 204.0601.
1
in 0.161 mmol, 79% yield (38.8 mg/49.2 mg); yellow oil: H NMR
(CDCl3, 400 MHz) δ 7.31−7.28 (m, 1H), 7.26−7.21 (m, 1H), 7.15−
7.07 (m, 2H), 7.03−7.00 (m, 2H), 6.82−6.78 (m, 2H), 4.00 (s, 2H),
3.77 (s, 3H), 3.14 (sept, J = 6.8 Hz, 1H), 1.13 (d, J = 6.8 Hz, 6H); 13C
NMR (CDCl3, 125 MHz) δ 157.1, 147.2, 137.7, 133.4, 130.5, 129.6,
126.9, 125.7, 125.6, 113.8, 55.3, 38.0, 29.0, 23.9; IR (neat, cm−1) 3061,
2961, 2832, 1362, 1037, 805, 760; HRMS (FAB, positive) m/z calcd
for C17H20O 240.1514, found 240.1504.
Synthesis of 3-(4-Methoxybenzyl)thiophene (5m).19 To a
solution of diborylmethane 1 (110.8 mg, 0.41 mmol, 2 equiv), 1-
bromo-4-methoxybenzene (2c) (38.7 mg, 0.207 mmol), and Pd[P(t-
Bu)3]2 (10.2 mg, 20 μmol, 10 mol %) in dioxane (2.0 mL) was added
8 N KOH aq (50 μL, 0.4 mmol, 2 equiv) at room temperature. After 3
h stirring at room temperature, 8 N KOH aq (149 μL, 1.2 mmol, 6
equiv) and 3-bromothiophene (2s) (100.7 mg, 0.62 mmol, 3 equiv)
were added. The mixture was stirred at 60 °C for 16 h and passed
through a pad of silica gel with ether. Purification by silica gel column
chromatography (hexane/ether = 30/1) gave the product 5m in 0.192
Synthesis of 1-(4-Methoxybenzyl)-2-(trifluoromethyl)-
benzene (5i). To a solution of diborylmethane 1 (106.7 mg, 0.40
mmol, 2 equiv), 1-bromo-4-methoxybenzene (2c) (37.3 mg, 0.199
mmol), and Pd[P(t-Bu)3]2 (10.2 mg, 20 μmol, 10 mol %) in dioxane
(2.0 mL) was added 8 N KOH aq (48 μL, 0.4 mmol, 2 equiv) at room
temperature. After 3 h stirring at room temperature, 8 N KOH aq (144
μL, 1.2 mmol, 6 equiv) and 1-bromo-2-(trifluoromethyl)benzene (2p)
(133.1 mg, 0.59 mmol, 3 equiv) were added. The mixture was stirred
at 60 °C for 16 h and passed through a pad of silica gel with ether.
Purification by silica gel column chromatography (hexane/ether = 30/
1) gave the product 5i in 0.142 mmol, 71% yield (37.7 mg/53.1 mg);
1
mmol, 93% yield (39.2 mg/42.3 mg): H and 13C NMR chemical
shifts were literature known; IR (neat, cm−1) 3097, 3035, 2834, 1245,
1036, 813, 747; HRMS (FAB, positive) m/z calcd for C12H12OS
204.0609, found 204.0606.
Synthesis of 3-(4-Methoxybenzyl)furan (5n). To a solution of
diborylmethane 1 (109.1 mg, 0.41 mmol, 2 equiv), 1-bromo-4-
methoxybenzene (2c) (38.4 mg, 0.205 mmol), and Pd[P(t-Bu)3]2
(10.2 mg, 20 μmol, 10 mol %) in dioxane (2.0 mL) was added 8 N
KOH aq (49 μL, 0.4 mmol, 2 equiv) at room temperature. After 3 h
stirring at room temperature, 8 N KOH aq (148 μL, 1.2 mmol, 6
equiv) and 3-bromofuran (2t) (93.1 mg, 0.63 mmol, 3 equiv) were
added. The mixture was stirred at 60 °C for 16 h and passed through a
pad of silica gel with ether. Purification by silica gel column
chromatography (hexane/ether = 30/1) gave the product 5n in
0.152 mmol, 74% yield (28.7 mg/38.6 mg); orange oil: 1H NMR
(CDCl3, 400 MHz) δ 7.35 (s, 1H), 7.19 (s, 1H), 7.13 (m, J = 8.4 Hz,
2H), 6.84 (d, J = 8.4 Hz, 2H), 6.23 (s, 1H), 3.80 (s, 3H), 3.71 (s, 2H);
13C NMR (CDCl3, 125 MHz) δ 158.1, 143.1, 139.6, 132.5, 129.6,
1
yellow oil: H NMR (CDCl3, 400 MHz) δ 7.65 (d, J = 7.6 Hz, 1H),
7.42 (t, J = 7.6 Hz, 1H), 7.29 (t, J = 7.6 Hz, 1H), 7.14 (d, J = 7.6 Hz,
1H), 7.07 (d, J = 8.4 Hz, 2H), 6.84 (d, J = 8.4 Hz, 2H), 4.12 (s, 2H),
3.79 (s, 3H); 13C NMR (CDCl3, 125 MHz) δ 158.3, 140.1, 132.0,
131.8, 131.7, 130.2, 128.7 (J2 = 29.8 Hz), 126.2, 125.9 (J3 = 6.0 Hz),
124.7 (J1 = 274.1 Hz), 114.0, 55.3, 37.0 (J4 = 2.4 Hz); 19F NMR
(CDCl3, 466 MHz) δ −59.5; IR (neat, cm−1) 2929, 2843, 1247, 1121,
1037, 805, 767; HRMS (FAB, positive) m/z calcd for C15H13F3O
266.0918, found 266.0907.
Synthesis of 1-Methoxy-4-(2-nitrobenzyl)benzene (5j).18 To
a solution of diborylmethane 1 (105.7 mg, 0.39 mmol, 2 equiv), 1-
bromo-4-methoxybenzene (2c) (36.8 mg, 0.197 mmol), and Pd[P(t-
Bu)3]2 (10.2 mg, 20 μmol, 10 mol %) in dioxane (2.0 mL) was added
8 N KOH aq (47 μL, 0.4 mmol, 2 equiv) at room temperature. After 3
h stirring at room temperature, 8 N KOH aq (142 μL, 1.2 mmol, 6
equiv) and 1-bromo-2-nitrobenzene (2q) (119.1 mg, 0.59 mmol, 3
equiv) were added. The mixture was stirred at 60 °C for 16 h and
passed through a pad of silica gel with ether. Purification by silica gel
column chromatography (hexane/ether = 10/1) gave the product 5j in
124.8, 113.9, 111.3, 55.4, 30.4; IR (neat, cm−1) 3001, 2929, 2836,
1515, 1247, 874, 822, 754; HRMS (FAB, positive) m/z calcd for
C12H12O2 188.0837, found 188.0830.
Synthesis of 2-(4-Methoxybenzyl)pyridine (5o).20 To a
solution of diborylmethane 1 (107.3 mg, 0.40 mmol, 2 equiv), 1-
bromo-4-methoxybenzene (2c) (37.4 mg, 0.200 mmol), and Pd[P(t-
Bu)3]2 (10.2 mg, 20 μmol, 10 mol %) in dioxane (2.0 mL) was added
8 N KOH aq (48 μL, 0.4 mmol, 2 equiv) at room temperature. After 3
h stirring at room temperature, 8 N KOH aq (144 μL, 1.2 mmol, 6
equiv) and 2-bromopyridine (2u) (94.0 mg, 0.59 mmol, 3 equiv) were
added. The mixture was stirred at 60 °C for 21 h and passed through a
pad of silica gel with ether. Purification by silica gel column
chromatography (hexane/EtOAc = 10/1) gave the product 5o in
0.101 mmol, 50% yield (20.1 mg/39.8 mg).
1
0.120 mmol, 61% yield (29.1 mg/47.9 mg): H, 13C NMR chemical
shifts, and HRMS were literature known; IR (neat, cm−1) 2954, 2836,
1526, 1350, 1247, 1035, 862, 800, 766.
Synthesis of 1-(2,6-Dimethylbenzyl)-4-methoxybenzene
(5k). To a solution of diborylmethane 1 (106.3 mg, 0.40 mmol, 2
equiv), 1-bromo-4-methoxybenzene (2c) (37.1 mg, 0.198 mmol), and
Pd[P(t-Bu)3]2 (10.2 mg, 20 μmol, 10 mol %) in dioxane (2.0 mL) was
added 8 N KOH aq (48 μL, 0.4 mmol, 2 equiv) at room temperature.
After 3 h stirring at room temperature, 8 N KOH aq (143 μL, 1.2
mmol, 6 equiv) and 2-bromo-1,3-dimethylbenzene (2k) (107.8 mg,
0.58 mmol, 3 equiv) were added. The mixture was stirred at 60 °C for
16 h and passed through a pad of silica gel with ether. Purification by
silica gel column chromatography (hexane/ether = 30/1) gave the
product 5k in 0.145 mmol, 73% yield (32.9 mg/44.9 mg); white solid:
mp 61 °C; 1H NMR (CDCl3, 400 MHz) δ 7.12−7.03 (m, 3H), 6.93−
6.91 (m, 2H), 6.80−6.76 (m, 2H), 3.99 (s, 2H), 3.76 (s, 3H), 2.24 (s,
6H); 13C NMR (CDCl3, 125 MHz) δ 157.8, 137.4, 137.2, 131.8,
128.9, 128.2, 126.4, 113.9, 55.3, 34.2, 20.3; IR (neat, cm−1) 2947,
2834, 1511, 1246, 1038, 769; HRMS (FAB, positive) m/z calcd for
C16H18O 226.1358, found 226.1358.
Synthesis of 3-(4-Methoxybenzyl)pyridine (5p). To a solution
of diborylmethane 1 (105.0 mg, 0.39 mmol, 2 equiv), 1-bromo-4-
methoxybenzene (2c) (36.6 mg, 0.196 mmol), and Pd[P(t-Bu)3]2
(10.2 mg, 20 μmol, 10 mol %) in dioxane (2.0 mL) was added 8 N
KOH aq (47 μL, 0.4 mmol, 2 equiv) at room temperature. After 3 h
stirring at room temperature, 8 N KOH aq (141 μL, 1.2 mmol, 6
equiv) and 3-bromopyridine (2v) (92.1 mg, 0.58 mmol, 3 equiv) were
added. The mixture was stirred at 60 °C for 16 h and passed through a
pad of silica gel with ether. Purification by silica gel column
chromatography (hexane/EtOAc = 10/1) gave the product 5p in
0.156 mmol, 80% yield (31.0 mg/39.0 mg); yellow oil: 1H NMR
(CDCl3, 400 MHz) δ 8.50−8.44 (m, 2H), 7.47−7.43 (m, 1H), 7.22−
7.18 (m, 1H), 7.11−7.08 (m, 2H), 6.86−6.83 (m, 2H), 3.92 (s, 2H),
3.79 (s, 3H); 13C NMR (CDCl3, 125 MHz) δ 158.3, 150.2, 147.7,
137.0, 136.3, 132.0, 129.9, 123.5, 114.2, 55.4, 38.3; IR (neat, cm−1)
3001, 2929, 2835, 1515, 1250, 806, 711; HRMS (FAB, positive) m/z
calcd for C13H13NO 199.0997, found 199.1002.
Synthesis of 2-(4-Methoxybenzyl)thiophene (5l).17 To a
solution of diborylmethane 1 (106.0 mg, 0.40 mmol, 2 equiv), 1-
bromo-4-methoxybenzene (2c) (37.0 mg, 0.198 mmol), and Pd[P(t-
Bu)3]2 (10.3 mg, 20 μmol, 10 mol %) in dioxane (2.0 mL) was added
8 N KOH aq (48 μL, 0.4 mmol, 2 equiv) at room temperature. After 3
Synthesis of 1-Methyl-4-[4-(trifluoromethyl)benzyl]benzene
(5q).8 To a solution of diborylmethane 1 (108.1 mg, 0.40 mmol, 2
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dx.doi.org/10.1021/jo3015165 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Featured Article
equiv), 1-bromo-4-methylbenzene (2a) (34.5 mg, 0.202 mmol), and
Pd[P(t-Bu)3]2 (10.2 mg, 20 μmol, 10 mol %) in dioxane (2.0 mL) was
added 8 N KOH aq (48 μL, 0.4 mmol, 2 equiv) at room temperature.
After 7 h stirring at room temperature, 8 N KOH aq (145 μL, 1.2
mmol, 6 equiv) and 1-bromo-4-(trifluoromethyl)benzene (2m) (134.2
mg, 0.60 mmol, 3 equiv) were added. The mixture was stirred at 60 °C
for 16 h and passed through a pad of silica gel with ether. Purification
by silica gel column chromatography (hexane) gave the product 5q in
0.177 mmol, 88% yield (44.2 mg/50.5 mg); colorless oil: 1H, 13C
NMR chemical shifts, and HRMS were literature known; 19F NMR
(CDCl3, 466 MHz) δ −62.2; IR (neat, cm−1) 2925, 2861, 1515, 1124,
1066, 797.
pad of silica gel with ether. Concentration gave the residue, the NMR
yield of which was determined to be 74% by the integration ratio of
the crude NMR with 1,1,2,2-tetrachloroethane as an internal standard.
Purification by silica gel column chromatography (hexane/ether = 30/
1) gave the product 7a in 0.133 mmol, 67% yield (28.3 mg/42.1 mg);
white solid: mp 56 °C.
Synthesis of (E)-1-Methoxy-4-(4-phenylbut-3-en-1-yl)-
benzene (7b). To a solution of diborylmethane 1 (105.6 mg, 0.39
mmol, 2 equiv), 1-bromo-4-methoxybenzene (2d) (36.9 mg, 0.197
mmol), and Pd[P(t-Bu)3]2 (10.2 mg, 20 μmol, 10 mol %) in dioxane
(2.0 mL) was added 8 N KOH aq (47 μL, 0.4 mmol, 2 equiv) at room
temperature. After 3 h stirring at room temperature, 8 N KOH aq (142
μL, 1.2 mmol, 6 equiv) and cinnamyl bromide (6b) (116.0 mg, 0.59
mmol, 3 equiv) were added. The mixture was stirred at 60 °C for 24 h
and passed through a pad of silica gel with ether. Concentration gave
the residue, the NMR yield of which was determined to be 49% by the
integration ratio of the crude NMR with 1,1,2,2-tetrachloroethane as
an internal standard. Purification by silica gel column chromatography
(hexane/ether = 30/1) gave the product 7b in 0.093 mmol, 47% yield
Synthesis of 3-(4-Methylbenzyl)thiophene (5r).19 To a
solution of diborylmethane 1 (106.7 mg, 0.40 mmol, 2 equiv), 1-
bromo-4-methylbenzene (2a) (34.0 mg, 0.199 mmol), and Pd[P(t-
Bu)3]2 (10.2 mg, 20 μmol, 10 mol %) in dioxane (2.0 mL) was added
8 N KOH aq (48 μL, 0.4 mmol, 2 equiv) at room temperature. After 7
h stirring at room temperature, 8 N KOH aq (143 μL, 1.2 mmol, 6
equiv) and 3-bromothiophene (2s) (98.2 mg, 0.62 mmol, 3 equiv)
were added. The mixture was stirred at 60 °C for 16 h and passed
through a pad of silica gel with ether. Purification by silica gel column
chromatography (hexane) gave the product 5r in 0.163 mmol, 82%
1
(22.1 mg/47.0 mg); yellow solid: mp 69 °C; H NMR (CDCl3, 400
MHz) δ 7.35−7.25 (m, 4H), 7.21−7.11 (m, 3H), 6.84 (d, J = 8.5 Hz,
2H), 6.41 (d, J = 15.6 Hz, 1H), 6.25 (dt, J = 15.6, 6.8 Hz, 1H), 3.79 (s,
3H), 2.73 (t, J = 7.2 Hz, 2H), 2.49 (q, J = 7.2 Hz, 2H); 13C NMR
(CDCl3, 100 MHz) δ 157.8, 137.7, 133.8, 130.3, 130.1, 129.3, 128.5,
126.9, 126.0, 113.8, 55.2, 35.1, 34.9; IR (neat, cm−1) 2928, 2885, 2835,
1448, 1246, 1037, 816, 748; HRMS (FAB, positive) m/z calcd for
C17H18O 238.1350, found 238.1358.
1
yield (30.6 mg/37.4 mg); yellow oil: H, 13C NMR chemical shifts
were literature known; IR (neat, cm−1) 2921, 2856, 1021, 766, 745;
HRMS (FAB, positive) m/z calcd for C12H12S 188.0660, found
188.0652.
Synthesis of 1-Fluoro-4-(4-(trifluoromethyl)benzyl)benzene
(5s). To a solution of diborylmethane 1 (104.8 mg, 0.39 mmol, 2
equiv), 1-bromo-4-fluorobenzene (2d) (34.2 mg, 0.195 mmol), and
Pd[P(t-Bu)3]2 (10.2 mg, 20 μmol, 10 mol %) in dioxane (2.0 mL) was
added 8 N KOH aq (47 μL, 0.4 mmol, 2 equiv) at room temperature.
After 4 h stirring at room temperature, 8 N KOH aq (141 μL, 1.2
mmol, 6 equiv) and 1-bromo-4-(trifluoromethyl)benzene (2m) (131.9
mg, 0.59 mmol, 3 equiv) were added. The mixture was stirred at 60 °C
for 16 h and filtered through a pad of silica gel with ether. Purification
by silica gel column chromatography (hexane) gave the product 5s in
ASSOCIATED CONTENT
■
S
* Supporting Information
NMR spectra of products. This material is available free of
charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: kendo@se.kanazawa-u.ac.jp; tshibata@waseda.jp.
1
0.150 mmol, 77% yield (38.1 mg/49.7 mg); colorless oil: H NMR
(CDCl3, 400 MHz) δ 7.54 (d, J = 8.0 Hz, 2H), 7.29−7.24 (m, 2H),
7.15−7.10 (m, 2H), 7.01−6.95 (m, 2H), 4.00 (s, 2H); 13C NMR
(CDCl3, 125 MHz) δ 161.7 (J1 = 244.3 Hz), 145.1, 135.7 (J4 = 2.4
Hz), 130.4 (J3 = 8.3 Hz), 129.2, 128.7 (J′2 = 32.2), 125.6 (J′4 = 3.6
Hz), 124.3 (J′1 = 270.5 Hz), 115.6 (J2 = 21.5 Hz), 40.9; 19F NMR
(CDCl3, 466 MHz) δ −62.3; IR (neat, cm−1) 2927, 2856, 1327, 1160,
1124, 817; HRMS (FAB, positive) m/z calcd for C14H11F4 [M + H]+
255.0797, found 255.0786.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by JST PRESTO program, Grant-in-
Aid for Young Scientists (B) from the Japan Society for the
Promotion of Science.
Synthesis of 1-Methoxy-2-(2-methylbenzyl)benzene (5t). To
a solution of diborylmethane 1 (105.7 mg, 0.39 mmol, 2 equiv), 1-
bromo-2-methoxybenzene (2i) (36.9 mg, 0.197 mmol), and Pd[P(t-
Bu)3]2 (10.2 mg, 20 μmol, 10 mol %) in dioxane (2.0 mL) was added
8 N KOH aq (47 μL, 0.4 mmol, 2 equiv) at room temperature. After 5
h stirring at room temperature, 8 N KOH aq (142 μL, 1.2 mmol, 6
equiv) and 1-bromo-2-methylbenzene (2h) (100.3 mg, 0.59 mmol, 3
equiv) were added. The mixture was stirred at 60 °C for 16 h and
passed through a pad of silica gel with ether. Purification by silica gel
column chromatography (hexane/ether = 30/1) gave the product 5t in
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dx.doi.org/10.1021/jo3015165 | J. Org. Chem. XXXX, XXX, XXX−XXX

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dx.doi.org/10.1021/jo3015165 | J. Org. Chem. XXXX, XXX, XXX−XXX