Selective Monoarylation of Aromatic Ketones via C-H Bond Cleavage by Trialkylphosphine Ruthenium Catalysts

Article abstract of DOI:10.1021/acs.joc.9b01756

A catalyst system consisting of RuHCl(CO)(PⁱPr₃)₂, CsF, and a styrene derivative was found to be applicable to selective monoarylation of aromatic ketones via ortho C-H bond cleavage. The reaction of 2′-methoxyacetophenone

Full text of DOI:10.1021/acs.joc.9b01756

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Article
Selective Monoarylation of Aromatic Ketones via C–H
Bond Cleavage by Trialkylphosphine Ruthenium Catalysts
Issei Suzuki, Hikaru Kondo, Takuya Kochi, and Fumitoshi Kakiuchi
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b01756 • Publication Date (Web): 19 Sep 2019
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Selective Monoarylation of Aromatic Ketones via C–H Bond Cleavage by
Trialkylphosphine Ruthenium Catalysts
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Issei Suzuki, Hikaru Kondo, Takuya Kochi, and Fumitoshi Kakiuchi*
Department of Chemistry, Faculty of Science and Technology, Keio University, 3-14-1 Hiyoshi,
Kohoku-ku, Yokohama, Kanagawa 223-8522, Japan.
kakiuchi@chem.keio.ac.jp
Table of Contents/Abstract Graphic
Abstract
A catalyst system consisting of RuHCl(CO)(PiPr3)2, CsF, and a styrene derivative was found
applicable to selective monoarylation of aromatic ketones via ortho C–H bond cleavage. The
reaction of 2’-methoxyacetophenone with arylboronates gave C–H arylation products without
cleaving the ortho C–O bond. Acetophenone was also converted to monoarylation products with
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high selectivity. Cyclohexanone was found as an effective solvent for the C–H arylation using
the catalyst system.
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Introduction
Catalytic bond formation via cleavage of unreactive bonds by transition metal complexes have
become a powerful tool in organic synthesis, and conversion of diverse types of C–H and C–
heteroatom bonds have been achieved using a variety of transition metal catalysts.1,2 When there
are more than one cleavable bond present in substrates, however, selective cleavage of one
particular bond and its conversion may be challenging.3 Our group have reported that
RuH2(CO)(PPh3)3 can be used as a catalyst for various types of arylation of aromatic ketones
with arylboronates via cleavage of ortho C–H, C–O, C–N, and C–F bonds (Figures 1a and 1b),4-7
but arylation of aromatic ketones having two cleavable bonds at ortho positions generally
provides diarylation products (Figure 1c).5 For this catalyst system, it is considered that after the
formation of intermediate A by the first cleavage and transformation of a bond at the other ortho
position, the second cleavage of a bond at an ortho position to give intermediate B is faster than
dissociation of monoarylation product C from the metal center (Figure 1d). Investigation of
methods for selective monoarylation of aromatic ketones was then explored using ruthenium
catalysts. For the reaction of aromatic ketones having two ortho C–H bonds, addition of styrene
was found to improve the selectivity towards monoarylation (Scheme 1a).3c Recently, we also
found that selective monoarylation of aromatic ketones bearing two ortho carbon-heteroatom
bonds such as C–O and C–N bonds can be achieved using a catalyst system consisting of
RuHCl(CO)(PiPr3)2, CsF, and styrene (Scheme 1b).6d The high selectivity toward monoarylation
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prompted us to examine its application to selective monoarylation of other types of aromatic
ketones.
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Figure 1. RuH2(CO)(PPh3)3-catalyzed ortho-selective arylation of aromatic ketones with
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arylboronates via C–H and C–heteroatom bond cleavage
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Scheme 1. Ruthenium-catalyzed selective monoarylation of aromatic ketones
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Herein we report that selective monoarylation via C–H bond cleavage is achieved for 2’-
methoxyacetophenone and acetophenone using catalyst systems consisting of
RuHCl(CO)(PiPr3)2, CsF, and a styrene derivative. The reaction of 2’-methoxyacetophenone
selectively gave the C–H arylation product with maintaining the C–O bond (Scheme 1c). The C–
H arylation of acetophenone provided monoarylation products in higher yields than those
prepared using the previously-reported catalyst system involving RuH2(CO)(PPh3)3 and styrene
(Scheme 1d). Cyclohexanone, an inexpensive, relatively high-boiling point solvent, was found as
the most suitable solvent for both of the C–H monoarylation reactions using this catalyst system.
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Results and Discussion
The reaction of 2’-methoxyacetophenone 1a was first examined. Previously, ketone 1a was
used for selective monoalkenylation via ortho C–H bond cleavage using RuH2(CO)(PPh3)3 as a
catalyst. In the alkenylation, coordination of the alkenyl group in the monoalkenylation product
is considered to effectively inhibit the C–O bond cleavage and to suppress the formation of the
dialkenylation product. Selective monoarylation of ketone 1a via C–H bond cleavage was
difficult to achieve by using RuH2(CO)(PPh3)3 because of the rapid diarylation. For example,
when the reaction of 1a with 1.2 equiv of phenylboronate 2a was conducted in the presence of 4
mol % of RuH2(CO)(PPh3)3 in pinacolone at 100 ºC for 1 h, 46% yield of diarylation product 5a
was obtained as a major product and only small amounts of monoarylation products 3a and 4a
were observed. (Scheme 2a). Selective C–H arylation of 2-methoxyaryl ketones was reported by
Lu, Sun, and coworkers using a Cp*Rh(III) catalyst,3i but the examples only included the
reaction of ketones having an isopropyl group, and the reactions of acetophenone derivatives
were not described (Scheme 2b).
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Scheme 2. Catalytic arylations of 2-methoxyaryl ketones
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When the reaction of ketone 1a with 1.2 equiv of phenylboronate 2a was performed in the
presence of 4 mol % of RuHCl(CO)(PiPr3)2 (6a), 8 mol % of CsF, and 1 equiv of styrene (7a) in
pinacolone for 1 h at 100 ºC, C–H arylation product 3a was formed in 59% GC yield along with
4% GC yield of C–O arylation product 4a and 33% GC yield of C–H/C–O diarylation product 5a
(Scheme 3). In order to improve the selectivity toward 3a, the reaction conditions were examined.
Lowering of the temperature to 70 ºC suppressed the formations of 4a and 5a with providing 3a
in 42% GC yield. Extension of the reaction time to 3 h led to the increase of the yield of 3a to
84%, but the diarylation product 5a was also obtained in 8% yield. The use of other
trialkylphosphine ruthenium complexes, RuHCl(CO)(PtBu2Me)2 (6b) and RuHCl(CO)(PCy3)2
(6c) as a catalyst resulted in reduction of the yield of 3a.
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Scheme 3. Chemoselective C–H arylation of 2’-methoxyacetophenone (1a) with arylboronate 2a
by triisopropylphosphine ruthenium catalyst 6a
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In order to achieve further improvement of the selectivity toward 3a, ketone solvents, which
also function as hydride acceptors, other than pinacolone were examined for the arylation (Table
1). The reactions in various ketones were initially performed for 1 h to compare the catalytic
activity and the selectivity before the reaction reached full conversion of 1a. In all of the ketones
shown in Table 1, the reaction gave less than a trace amount of C–O arylation product 4a. The
reaction in acetone gave 3a in 51% yield with only a trace amount of 5a (entry 1). The use of 3-
methylbutan-2-one slightly improve the yield of 3a to 56%, but the amount of 5a was also
increased (entry 2), while reduction of the yield to 32% was observed for the reaction in 2-
heptanone (entry 3). Examination of cyclic ketones (entries 4-6) showed that cyclohexanone is
an effective solvent and provided 3a in 71% yield with an excellent material balance (entry 5).
Introduction of a methyl group at an α-position of cyclohexanone improved the yield of 3a to
89% with generating 5a in 3% yield (entry 7), but the reaction in 2,6-dimethylcyclohexanone
lowered the yield of 3a significantly (entry 8). Finally, elongation of the reaction time was
investigated for ketone solvents giving promising results such as acetone and cyclohexanone
(entries 9 and 10), and the reaction for 3 h in cyclohexanone was found to provide 3a in 92% GC
yield (entry 10).
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Table 1. Screening of Solvents for Chemoselective C–H Arylation of 1a with 2a by Catalyst
6aa
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Entry
solvent
time conversion of 1 (%)
GC yield (%)
(h)
3a
51
56
32
27
71
20
89
38
88
92
5a
trace
1
1
2
acetone
3-methylbutan-2-one
2-heptanone
1
1
1
1
1
1
1
1
3
3
59
68
42
32
73
31
97
53
92
96
3
trace
trace
trace
ndb
3
4
cyclopentanone
cyclohexanone
5
6
cycloheptanone
2-methylcyclohexanone
2,6-dimethylcyclohexanone
acetone
7
8
trace
1
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10
cyclohexanone
2
aReaction conditions: 1a (0.5 mmol), 2a (0.6 mmol), 6a (0.02 mmol), CsF (0.04 mmol), 7a (0.5
mmol), solvent (0.5 mL), 70 ºC. bNot detected.
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The chemoselective C–H arylation of 1a was applicable to various arylboronates and
monoarylation products were isolated in high yields (Table 2). Phenylation product 3a was first
conducted and obtained in 88% yield (entry 1). The reaction with arylboronates possessing
electron-donating groups including dimethylamino (2b), methoxy (2c), and methyl (2d) groups
at the para position gave the corresponding C–H arylation products 3b-d in 80-94% yields
(entries 2-4). The arylation can be performed with arylboronates possessing a halogeno group
such as bromo (2e) and chloro (2f) groups to provide 3e and 3f in high yields (entries 5 and 6).
The reaction also proceeded with 4-trifluoromethylphenylboronate 2g to afford biaryl 3g in 78%
yield (entry 7). 2-Naphthylboronate 2h can also be used for the C–H arylation to give 3h in 81%
yield (entry 8). The C–H arylation was also conducted using 2’,4’-dimethoxyacetophenone 1b
and phenylboronate 2a and the corresponding C–H phenylation product 3i was obtained in 85%
yield (Scheme 4). The reaction of 2’-(N,N-dimethylamino)acetophenone was also examined but
gave a complex mixture of products including the corresponding monoarylation and diarylation
products.
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Table 2. Chemoselective C–H Arylation of 1a with Various Arylboronates 2 by Catalyst 6aa
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entry
2
Ar
3
yield (%)
1
2b
3
2a
2b
2c
2d
2e
2f
Ph
3a
3b
3c
3d
3e
3f
88
80
94
89
83
91
78
81
4-Me2NC6H4
4-MeOC6H4
4-MeC6H4
4-ClC6H4
4-BrC6H4
4-F3CC6H4
2-naphthyl
4
5
6
7
2g
2h
3g
3h
8
aReaction conditions: 1a (0.5 mmol), 2a (0.6 mmol), 6a (0.02 mmol), CsF (0.04 mmol), 7a (0.5
mmol), cyclohexanone (0.5 mL). b Performed for 18 h.
Scheme 4. Chemoselective C–H phenylation of 2’,4’-dimethoxyacetophenone (1b)
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Selective C–H monoarylation of parent acetophenone 8a was then investigated. The reaction
was previously examined using RuH2(CO)(PPh3)3 as a catalyst and styrene as an additive, and
when arylboronate 2a was reacted with 3 equiv of 8a, monoarylation product 4a was obtained in
56% yield along with diarylation product 5a (Scheme 1a). Therefore, the monoarylation was
examined using a 3:1 ratio of ketone 8a and arylboronate 2a in the presence of trialkylphosphine
ruthenium complex, CsF, and styrene derivatives to compare the results with the previous
catalyst system.
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When the reaction was examined using 2.5 mol % of catalyst 6a, 5 mol % of CsF, and 1 equiv
of 7a in pinacolone for 2 h at 130 ºC (oil bath temp), monoarylation product 4a was formed in
70% GC yield, which is already higher than the previous catalyst system (Scheme 1a), along
with 8% GC yield of diarylation product 5a (Table 3, entry 1). Catalysts 6b and 6c were then
tested for the reaction but resulted in lower yields (entries 2 and 3). Because the use of
cyclohexanone improved the material balance between substrate 1a and arylation products 3a
and 5a in the C–H arylation (Table 1, entry 10), the phenylation of 8a was examined in
cyclohexanone. As a result, monoarylation product 4a was obtained in slightly lower yield (65%),
but the material balance between substrate 8a and products 4a and 5a was again improved (entry
4). In order to enhance the π-accepting ability, introduction of electronegative substituents was
also explored, and it was found that the yield of 4a was affected by introduction of
electronegative substituents on the styrene additive (entries 5-8). Particularly, the reaction in the
presence of 4-trifluoromethylstyrene (7d) or 2,3,4,5,6-pentafluorostyrene (7e) provided
monoarylation product 4a in 77% yield (entries 7 and 8). Since the reaction using 7e gave
slightly less diarylation product 5a than that using 7d, further examination of the reaction was
conducted using 7e as an additive.
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Table 3. Selective C–H Monoarylation of Acetophenone (8a) with 2a by Trialkylphosphine
Ruthenium Catalysts 6a
7
8
9
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entry RuHCl(CO)(PR3)2 6
styrene 7
solvent
conversion GC yields (%)
of 8 (%)
>99
63
4a
70
51
60
65
60
5a
8
1
2
3
4
5
6a (PR3 = PiPr3)
7a
7a
7a
7a
pinacolone
pinacolone
6b (PR3 = PtBu2Me)
6
6c (PR3 = PCy3)
pinacolone
87
6
6a
6a
cyclohexanone
cyclohexanone
>99
>99
30
34
6
7
6a
6a
cyclohexanone
cyclohexanone
>99
99
69
77
23
15
8
6a
cyclohexanone
97
77
13
aReaction conditions: 8a (3 mmol), 2a (1 mmol), 6 (0.025 mmol), CsF (0.05 mmol), 7 (1 mmol),
solvent (1 mL), 130 ºC.
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The improved conditions for C–H monoarylation was applied to the reaction with various
arylboronates (Table 4). The reactions with 2b-2d were not completed in 2 h, but elongation of
the reaction time to 4 h led to the formation of the corresponding monoarylation products 4b-4d
in 67-74% isolated yields (entries 1-3). The reaction with 4-fluoro-, 4-chloro-, and 4-
bromophenylboronates (2j , 2e, and 2f) also monoarylation products 4j, 4e, and 4f as major
products as well, but the mono-/diarylation ratios were decreased as the electron-withdrawing
ability of the 4-substituent increased (entries 4-6). The arylation of 8a with 4-
trifluoromethylboronate 2g also proceeded to give 56% yield of monoarylation product 4g and
28% yield of diarylation product 5g (entry 7). It is worth noting that using this catalyst system,
monoarylation products 4 were generally obtained in higher yields than the previous systems
employing RuH2(CO)(PPh3)3 and styrene (71% isolated yields for 4b, 67% isolated yield for 4c,
41% GC yield for 4j, and 33% GC yield for 4g). The reaction was applicable to the introduction
of the 2-naphthyl group and afforded 4h and 5h in 69 and 19% yields, respectively (entry 8). The
C–H arylation was also conducted using 4’-methoxyacetophenone 8b and phenylboronate 2a
(Scheme 5). The mono/diarylation selectivity was lowered in this case, and the corresponding C–
H monophenylation product 4i was obtained in 51% NMR yield along with 35% NMR yield of
diphenylation product 5i.
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Table 4. Selective C–H Monoarylation of 8a with Various Arylboronates 2 by Catalyst 6aa
5
6
7
8
9
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Entry
2
Ar
time (h)
yields (%)
4
5
1
2
3
4
5
6
7
8
2b
2c
2d
2j
4-Me2NC6H4
4-MeOC6H4
4-MeC6H4
4-FC6H4
4
4
4
2
2
2
2
2
74 (4b)
74 (4c)
67 (4d)
67 (4j)
66 (4e)
46 (4f)
56 (4g)
69 (4h)
ndb (5b)
12 (5c)
15 (5d)
20 (5j)
25 (5e)
22 (5f)
28 (5g)
19 (5h)
2e
2f
4-ClC6H4
4-BrC6H4
2g
2h
4-F3CC6H4
2-naphthyl
aReaction conditions: 8a (3 mmol), 2a (1 mmol), 6a (0.025 mmol), CsF (0.05 mmol), 7e (1
mmol), cyclohexanone (1 mL), 130 ºC. bNot detected.
Scheme 5. C–H arylation of 4’-methoxyacetophenone 8b with phenylboronate 2a
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Conclusions
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In summary, the catalyst system consisting of triisopropylphosphine ruthenium complex 6a,
CsF and a styrene derivative was found to be applicable to chemoselective C–H arylation of
ortho-methoxylated acetophenones 1 and C–H monoarylation of ortho-unsubstituted
acetophenones 8. Various arylboronates were found applicable to the reaction of 1a to provide
the C–H arylation products in high yields with keeping the C–O bond intact. The C–H arylation
of 8a with a variety of arylboronates provided monoarylation products in higher yields than the
reaction using the previously-reported RuH2(CO)(PPh3)3/styrene catalyst system. Cyclohexanone
as a solvent improved the material balance between substrates and was found to be the most
suitable solvent for both of the C–H arylation reactions.
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Experimental Section
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Unless otherwise noted, all reactions were carried out under nitrogen, and commercial
reagents were used as received. Aromatic ketones 1a and 8a were purchased from Nacalai
Tesque, Inc. and dried from CaCl2 and distilled under nitrogen. Aromatic ketones 1b and 8b
were purchased from Tokyo Chemical Industry Co., Ltd. and Nacalai Tesque, Inc. respectively
and recrystallized from hexane prior to use. Arylboronates 2a-d, 2g, 2h, 2j,8 2e9 and 2f10 were
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prepared
according
to
the
literature
procedures.
RuHCl(CO)(PiPr3)2
(6a),11
RuHCl(CO)(PtBu2Me)2 (6b)12 and RuHCl(CO)(PCy3)2 (6c)13 were prepared according to the
literature procedures. CsF was purchased from Nacalai Tesque, Inc. and used as received.
Styrenes 7a-e were dried from CaH2 and distilled under nitrogen prior to use. Anhydrous
acetone was purchased from FUJIFILM Wako Pure Chemical Corporation and used as received.
All ketone solvents except for acetone were dried from CaSO4 and distilled under nitrogen.
Styrenes 7a-d and cyclohexanone were purchased from Nacalai Tesque, Inc. Styrene derivative
7e, 3-methylbutan-2-one, cyclopentanone, cycloheptanone, 2-methylcyclohexanone, and 2,6-
dimethylcyclohexanone were purchased from Tokyo Chemical Industry Co., Ltd. Pinacolone
was purchased from FUJIFILM Wako Pure Chemical Corporation. 2-Heptanone was purchased
from Kanto Chemical Co. Inc. 1H NMR spectra were recorded on a JEOL ECX-400, AL-400, or
ALPHA-400 spectrometer. GC analysis was performed using a Shimazu GC-2014 equipped with
a CBP-10 capillary column (25 m × 0.22 mm, film thickness 0.25 μm). The temperature for GC
analysis was programmed from 70 to 250 °C at 10 °C/min ramp with a final hold time of 30 min
(injection temperature, 250 °C; detector temperature, 250 °C). Flash chromatography was carried
out with aluminium oxide 90 active basic (Merck Millipore), silica gel 60N (Kanto Chemical Co.,
Inc.), or using an EPCLC-AI-580S (Yamazen Corporation) with silica gel 40 μm.
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Optimization of Reaction Conditions for Chemoselective C–H Arylation of 2’-
Methoxyacetophenone (1a) with Arylboronate 2a by Trialkylphosphine Ruthenium
Catalyst 6. Ruthenium complex 6 (0.02 mmol, 4 mol %) and phenylboronate 2a (114 mg, 0.6
mmol, 1.2 equiv) were placed in an oven-dried sealed tube containing a magnetic stirring bar and
the tube was transferred into the glove box. CsF (6 mg, 0.04 mmol, 8 mol %), 2’-
methoxyacetophenone 1a (75 mg, 0.5 mmol), styrene 7a (52 mg, 0.5 mmol, 1 equiv) and 0.5 mL
of the ketone solvent were added to the mixture. After taken out of the glove box, the mixture
was stirred at 60-100 ºC using an oil bath for 1-24 h. The mixture was then cooled to room
temperature and volatile materials were removed by rotary evaporation. n-Hexadecane was
added as an internal standard to the mixture, which was then dissolved in AcOEt. The yield was
determined by gas chromatography (GC). The crude material was passed through a basic
aluminium oxide column to remove the remaining arylboronate. Further purification of the
product was performed by silica gel column chromatography.
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General Procedure A for Chemoselective C–H Arylation of 1 with Various Arylboronates
2 by Catalyst 6a. RuHCl(CO)(PiPr3)2 6a (10 mg, 0.02 mmol, 4 mol %) and arylboronate 2 (0.6
mmol, 1.2 equiv) were placed in an oven-dried sealed tube containing a magnetic stirring bar and
the tube was transferred into the glove box. CsF (6 mg, 0.04 mmol, 8 mol %), 2’-
methoxyacetophenone 1a or 2’,4’-dimethoxyacetophenone 1b (0.5 mmol), styrene 7a (52 mg,
0.5 mmol, 1 equiv) and 0.5 mL of cyclohexanone were added to the mixture. After taken out of
the glove box, the mixture was stirred at 70 ℃ using an oil bath for 3-18 h. The mixture was then
cooled to room temperature and volatile materials were removed by rotary evaporation. The
crude material was passed through a basic aluminium oxide column to remove the remaining
arylboronate. Further purification of the product was performed by silica gel column
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chromatography. H NMR spectra of the isolated products were in good agreement with those
5
6
reported in literature.
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8
9
1-(3-Methoxy-[1,1'-biphenyl]-2-yl)ethan-1-one (3a).6d General Procedure A was followed
with 1a (74.7 mg, 0.497 mmol) and 2a (115.5 mg, 0.608 mmol). Silica gel column
chromatography (hexane:AcOEt = 20:1) afforded 99.3 mg of 3a (0.439 mmol, 88% yield) as a
white solid.
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1-(4'-[Dimethylamino]-3-methoxy-[1,1'-biphenyl]-2-yl)ethan-1-one (3b).6d General Procedure
A (stirred for 18 h) was followed with 1a (74.3 mg, 0.495 mmol) and 2b (139.5 mg, 0.598
mmol). Silica gel column chromatography (hexane:AcOEt = 5:1) afforded 107 mg of 3b (0.395
mmol, 80% yield) as a white solid.
1-(3,4'-Dimethoxy-[1,1'-biphenyl]-2-yl)ethan-1-one (3c).6d General Procedure A was followed
with 1a (74.9 mg, 0.492 mmol) and 2c (133.8 mg, 0.608 mmol). Silica gel column
chromatography (hexane:AcOEt = 10:1) afforded 119 mg of 3c (0.464 mmol, 94% yield) as a
white solid.
1-(3-Methoxy-4'-methyl-[1,1'-biphenyl]-2-yl)ethan-1-one (3d).6d General Procedure A was
followed with 1a (73.6 mg, 0.490 mmol) and 2d (124.1 mg, 0.608 mmol). Silica gel column
chromatography (hexane:AcOEt = 20:1) afforded 105 mg of 3d (0.435 mmol, 89% yield) as a
white solid.
1-(4'-Chloro-3-methoxy-[1,1'-biphenyl]-2-yl)ethan-1-one (3e).6d General Procedure A was
followed with 1a (74.8 mg, 0.498 mmol) and 2e (133.3 mg, 0.593 mmol). Silica gel column
chromatography (hexane:AcOEt = 10:1) afforded 108 mg of 3e (0.416 mmol, 83% yield) as a
white solid.
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1-(4'-Bromo-3-methoxy-[1,1'-biphenyl]-2-yl)ethan-1-one (3f).6d General Procedure A was
followed with 1a (75.4 mg, 0.502 mmol) and 2f (160.8 mg, 0.598 mmol). Silica gel column
chromatography (hexane:AcOEt = 10:1) afforded 140 mg of 3f (0.457 mmol, 91% yield) as a
white solid.
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1-(3-Methoxy-4'-[trifluoromethyl]-[1,1'-biphenyl]-2-yl)ethan-1-one (3g).6d General Procedure
A was followed with 1a (75.6 mg, 0.503 mmol) and 2g (155.4 mg, 0.602 mmol). Silica gel
column chromatography (hexane:AcOEt = 10:1) afforded 115 mg of 3g (0.392 mmol, 78%
yield) as a white solid.
1-(2-Methoxy-6-(naphthalen-2-yl)phenyl)ethan-1-one (3h).6d General Procedure A was
followed with 1a (78.0 mg, 0.519 mmol) and 2h (145.8 mg, 0.607 mmol). Silica gel column
chromatography (hexane:AcOEt = 10:1) afforded 116 mg of 3h (0.420 mmol, 81% yield) as a
white solid.
1-(3,5-Dimethoxy-[1,1'-biphenyl]-2-yl)ethan-1-one (3i).6d General Procedure A was followed
with 1b (90.4 mg, 0.502 mmol) and 2b (115 mg, 0.605 mmol) and the reaction was performed
for 6 h. Silica gel column chromatography (hexane:AcOEt = 92:8), followed by Kugelrohr
distillation, afforded 109 mg of 3i (0.427 mmol, 85 % yield) as a white solid.
Optimization of Reaction Conditions for Selective C–H Monoarylation of Acetophenone
8a with Arylboronate 2a by Triisopropylphosphine Ruthenium Catalyst 6a.
RuHCl(CO)(PiPr3)2 6a (12 mg, 0.025 mmol, 2.5 mol %) and arylboronate 2a (190 mg, 1 mmol)
were placed in an oven-dried 10 mL Schlenk flask containing a magnetic stirring bar and the
tube was transferred into the glove box. CsF (8 mg, 0.05 mmol, 5 mol %), acetophenone 8a (360
mg, 3 mmol, 3 equiv), styrene derivative 7 (1 mmol, 1 equiv) and 1 mL of the ketone solvent
were added to the mixture. After taken out of the glove box, the mixture was stirred at 130 ℃
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using an oil bath for 2-6 h. The mixture was then cooled to room temperature and volatile
materials were removed by rotary evaporation. n-Hexadecane was added as an internal standard
to the mixture, which was then dissolved in AcOEt. The yield was determined by gas
chromatography (GC). The crude material was passed through a basic aluminium oxide column
to remove the remaining arylboronate. Further purification of the product was performed by
silica gel column chromatography.
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General Procedure B for Selective C–H Monoarylation of Acetophenone 8 with
Arylboronate 2 by Triisopropylphosphine Ruthenium Catalyst 6a. RuHCl(CO)(PiPr3)2 6a
(12 mg, 0.025 mmol, 2.5 mol %) and arylboronates 2 (1 mmol) were placed in an oven-dried 10
mL Schlenk flask containing a magnetic stirring bar and the tube was transferred into the glove
box. CsF (8 mg, 0.05 mmol, 5 mol %), acetophenone 8a or 4’-methoxyacetophenone 8b (3 mmol,
3 equiv), styrene derivative 7e (194 mg, 1 mmol, 1 equiv) and 1 mL of ketone solvent were
added to the mixture. The mixture was then stirred at 130 ℃ using an oil bath for 2-4 h. The
mixture was then cooled to room temperature and volatile materials were removed by rotary
evaporation. The crude material was passed through a basic aluminium oxide column to remove
the remaining arylboronate. Further purification of the product was performed by silica gel
column chromatography.
1-(4'-[Dimethylamino]-[1,1'-biphenyl]-2-yl)ethan-1-one (4b). General Procedure B was
followed with 8a (363 mg, 3.02 mmol) and 2b (235 mg, 1.01 mmol) and the reaction was
performed for 4 h. Silica gel column chromatography (hexane:AcOEt = 10:1) afforded 179 mg
1
of 4b (0.748 mmol, 74% yield) as a yellow oil. The H NMR spectrum of 4b was in good
agreement with that reported in literature.14
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1-(4'-Methoxy-[1,1'-biphenyl]-2-yl)ethan-1-one (4c) and 1-(4,4''-dimethoxy-[1,1':3',1''-
terphenyl]-2'-yl)ethan-1-one (5c). General Procedure B was followed with 8a (361 mg, 3.00
mmol) and 2c (221 mg, 1.00 mmol) and the reaction was performed for 4 h. Silica gel column
chromatography (hexane:AcOEt = 20:1) afforded 168 mg of 4c (0.744 mmol, 74% yield) as a
colorless oil and 19.9 mg of 5c (0.0599 mmol, 12% yield) as a white solid. The 1H NMR spectra
of 4c15 and 5c14 were in good agreement with those reported in literature.
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1-(4'-Methyl-[1,1'-biphenyl]-2-yl)ethan-1-one
(4d)
and
1-(4,4''-dimethyl-[1,1':3',1''-
terphenyl]-2'-yl)ethan-1-one (5d). General Procedure B was followed with 8a (371 mg, 3.08
mmol) and 2d (206 mg, 1.01 mmol) and the reaction was performed for 4 h. Silica gel column
chromatography (toluene:hexane:AcOEt = 40:20:1) afforded 142 mg of 4d (0.677 mmol, 67%
1
yield) as a colorless oil and 23.2 mg of 5d (0.0772 mmol, 15% yield) as a white solid. The H
1
NMR spectrum of 4d was in good agreement with that reported in literature.16 The H NMR
spectrum of 5d synthesized here was also in good agreement with that of 5d prepared by the
reaction of 8a with 2d using RuH2(CO)(PPh3)3 as a catalyst following General Procedure C.
1-(4'-Chloro-[1,1'-biphenyl]-2-yl)ethan-1-one
(4e)
and
1-(4,4''-dichloro-[1,1':3',1''-
terphenyl]-2'-yl)ethan-1-one (5e). General Procedure B was followed with 8a (368 mg, 3.06
mmol) and 2e (244 mg, 1.00 mmol) and the reaction was performed for 2 h. Silica gel column
chromatography (hexane:AcOEt = 96:4) afforded 153 mg of 4e (0.662 mmol, 66% yield) as a
colorless oil and 43.2 mg of 5e (0.127 mmol, 25% yield) as a white solid. The 1H NMR spectrum
of 4e was in good agreement with that reported in literature.17 Diarylation product 5e: mp 180-
182 °C; 1H NMR (400 MHz, CDCl3): δ 1.87 (s, 3 H), 7.27-7.50 (m, 10H), 7.49 (t, J = 8 Hz, 1H);
13C{1H} NMR (100 MHz, CDCl3): δ 33.0, 128.6, 128.9, 129.4, 130.4, 134.0, 137.8, 138.5, 141.1,
205.9; IR (KBr): 3745 w, 1698 s, 1594 w, 1492 s, 1449 m, 1397 m, 1351 m, 1244 m, 1179 w,
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1090 s, 1015 m, 850 m, 826 s, 763 m, 605 w, 532 m, 515 m cm-1; HRMS (ESI-TOF) m/z [M +
Na]+ calcd for C20H14Cl2NaO+ 363.0314, found 363.0315.
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1-(4'-Bromo-[1,1'-biphenyl]-2-yl)ethan-1-one (4f) and 1-(4,4''-dibromo-[1,1':3',1''-terphenyl]-
2'-yl)ethan-1-one (5f). General Procedure B was followed with 8a (362 mg, 3.01 mmol) and 2f
(267 mg, 0.994 mmol) and the reaction was performed for 2 h. Silica gel column
chromatography (toluene:hexane:AcOEt = 20:20:1) afforded 127 mg of 4f (0.461 mmol, 46%
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yield) as a colorless oil and 46.8 mg of 5f (0.109 mmol, 22% yield) as a white solid. The H
1
NMR spectrum of 4f was in good agreement with that reported in literature.18 The H NMR
spectrum of 5f synthesized here was also in good agreement with that of 5f prepared by the
reaction of 8a with 2f using RuH2(CO)(PPh3)3 as a catalyst following General Procedure C.
1-(4'-[Trifluoromethyl]-[1,1'-biphenyl]-2-yl)ethan-1-one
(4g)
and
1-(4,4''-
bis[trifluoromethyl]-[1,1':3',1''-terphenyl]-2'-yl)ethan-1-one (5g). General Procedure B was
followed with 8a (364 mg, 3.03 mmol) and 2g (258 mg, 1.00 mmol) and the reaction was
performed for 2 h. Silica gel column chromatography (hexane:AcOEt = 30:1) afforded 147 mg
of 4g (0.556 mmol, 56% yield) as a colorless oil and 58.0 mg of 5g (0.142 mmol, 28% yield) as a
1
white solid. The H NMR spectra of 4g and 5g were in good agreement with that reported in
literature.3c
1-(2-[Naphthalen-2-yl]phenyl)ethan-1-one (4h) and 1-(2,6-di[naphthalen-2-yl]phenyl)ethan-
1-one (5h). General Procedure B was followed with 8a (361 mg, 3.00 mmol) and 2h (240 mg,
1.00 mmol) and the reaction was performed for 2 h. Silica gel column chromatography
(toluene:hexane:AcOEt = 40:20:1) afforded 169 mg of 4h (0.686 mmol, 69% yield) as a
1
colorless oil and 35.6 mg of 5h (0.0956 mmol, 19% yield) as a white solid. The H NMR
spectrum of 4h was in good agreement with that reported in literature.19 The 1H NMR spectrum
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of 5h synthesized here was also in good agreement with that of 5h prepared by the reaction of 8a
with 2h using RuH2(CO)(PPh3)3 as a catalyst following General Procedure C.
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1-(5-Methoxy-[1,1'-biphenyl]-2-yl)ethan-1-one (4i) and and 1-(5'-methoxy-[1,1':3',1''-
terphenyl]-2'-yl)ethan-1-one (5i). General Procedure B was followed with 8b (455 mg, 3.03
mmol) and 2a (192 mg, 1.01 mmol) and the reaction was performed for 2 h. Silica gel column
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chromatography (hexane:AcOEt = 96:4) afforded 466 mg of a mixture of 4i, 5i and 8b. The H
NMR spectra of the mixture and its comparison with those of 4i,20 5i,5a and 8b21 reported in
literature suggested that the molar ratio of 4i, 5i and 8b is ca. 26:9:100, and the mixture contains
116 mg of 4i (0.51 mmol, 51% yield) and 54 mg of 5i (0.18 mmol, 35% yield).
1-(4'-Fluoro-[1,1'-biphenyl]-2-yl)ethan-1-one (4j) and 1-(4,4''-difluoro-[1,1':3',1''-terphenyl]-
2'-yl)ethan-1-one (5j). General Procedure B was followed with 8a (365 mg, 3.04 mmol) and 2j
(209 mg, 1.01 mmol) and the reaction was performed for 2 h. Silica gel column chromatography
(hexane:AcOEt = 30:1) afforded 143 mg of 4j (0.667 mmol, 67% yield) as a colorless oil and
1
31.2 mg of 5j (0.102 mmol, 20% yield) as a white solid. The H NMR spectra of 4j22 and 5j3c
were in good agreement with those reported in literature.
General Procedure C for C–H Diarylation of 8a with Arylboronates 2 Using
RuH2(CO)(PPh3)3 as a Catalyst. C–H diarylation products 5 were prepared by the reaction of
8a with 2 in the presence of 2.5 mol % of RuH2(CO)(PPh3)3 in pinacolone.5b RuH2(CO)(PPh3)3
(11.5 mg, 0.0125 mmol, 2.5 mol %) and arylboronates 2 (0.9 mmol, 1.8 equiv) were placed in an
oven-dried sealed tube containing a magnetic stirring bar and the tube was transferred into the
glove box. Acetophenone 8a (0.5 mmol), and 0.5 mL of pinacolone were added to the mixture.
After taken out of the glove box, the mixture was stirred at 120 ℃ for 16 h. The mixture was
then cooled to room temperature and volatile materials were removed by rotary evaporation. The
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crude material was passed through a basic aluminium oxide column to remove the remaining
arylboronate. Further purification of the product was performed by silica gel column
chromatography.
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1-(4,4''-Dimethyl-[1,1':3',1''-terphenyl]-2'-yl)ethan-1-one (5d). General Procedure C was
followed with 8a (60.1 mg, 0.500 mmol) and 2d (183 mg, 0.895 mmol). Silica gel column
chromatography (hexane:AcOEt = 97:3) afforded 18.8 mg of 5d (0.0626 mmol, 13% yield) as a
white solid: mp 136-137 °C; 1H NMR (400 MHz, CDCl3): δ 1.88 (s, 3H), 2.38 (s, 6H), 7.19-7.25
(m, 8H), 7.32 (d, J = 7.2 Hz, 2H), 7.45 (t, J = 7.8 Hz, 1 H); 13C{1H} NMR (100 MHz, CDCl3): δ
21.2, 33.0, 128.6, 128.9, 129.0, 129.1, 137.3, 137.4, 138.9, 141.2, 206.6; IR (KBr): 3026 w, 2919
w, 1908 w, 1703 s, 1512 m, 1451 m, 1412 w, 1348 m, 1238 m, 829 m, 800 s, 760 m, 518 s cm-1;
HRMS (ESI-TOF) m/z [M + K]+ calcd for C22H20KO+ 339.1146, found 339.1144.
1-(4,4''-Dibromo-[1,1':3',1''-terphenyl]-2'-yl)ethan-1-one (5f). General Procedure C was
followed with 8a (61.2 mg, 0.509 mmol) and 2f (244 mg, 0.908 mmol). Silica gel column
chromatography (hexane:AcOEt = 97:3) afforded 23.4 mg of 5f (0.0544 mmol, 11% yield) as a
1
white solid: mp 219-220 °C; H NMR (400 MHz, CDCl3): δ 1.88 (s, 3H), 7.21-7.24 (m, 4H),
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7.33 (d, J = 8.0 Hz, 2H), 7.48 (t, J = 12 Hz, 1H), 7.52-7.55(m, 4H); C{1H} NMR (100 MHz,
CDCl3): δ 33.0, 122.2, 128.9, 129.3, 130.7, 131.6, 137.8, 138.9, 141.0, 205.9; IR (KBr): 3067 w,
2919 w, 1067 w, 1705 s, 1589 w, 1489 m, 1449 m, 1389 m, 1349 w, 1243 m, 1008 m, 941 s, 603
w, 515 m cm-1; HRMS (ESI-TOF) m/z [M + Na]+ calcd for C20H14Br2NaO+ 452.9283, found
452.9277.
1-(2,6-Di[naphthalen-2-yl]phenyl)ethan-1-one (5h). General Procedure C was followed with
8a (64.0 mg, 0.533 mmol) and 2h (217 mg, 0.903 mmol). Silica gel column chromatography
(hexane:AcOEt = 97:3) afforded 105 mg of 5h (0.282 mmol, 53% yield) as a white solid: mp
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159-160 °C; 1H NMR (400 MHz, CDCl3): δ 1.87 (s, 3H), 7.47-7.57 (m, 9H), 7.85-7.89 (m, 8H);
13C{1H} NMR (100 MHz, CDCl3, 50 ℃): δ 32.9, 126.3, 126.5, 127.3, 127.7, 128.0, 128.2,
128.3, 128.7, 129.6, 132.7, 133.3, 137.9, 139.1, 141.9, 205.9; IR (KBr): 3053 m, 2919 w, 1695 s,
1598 w, 1505 w, 1349 m, 1242 m, 1133 w, 963 w, 894 m, 860 m, 823 s, 801 s, 750 s, 613 w, 480
s, 434 m s cm-1; HRMS (ESI-TOF) m/z [M + Na]+ calcd for C28H20NaO+ 395.1406, found
395.1407.
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Supporting Information
The Supporting Information is available free of charge on the ACS Publications website at
http://pubs.acs.org.
Additional data and copies of 1H and 13C{1H} NMR spectra (PDF)
Corresponding Author
*E-mail: kakiuchi@chem.keio.ac.jp
ORCID
Takuya Kochi: 0000-0002-5491-0566
Fumitoshi Kakiuchi: 0000-0003-2605-4675
Notes
The authors declare no competing financial interest.
Acknowledgements
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This work was supported in part by JSPS KAKENHI Grant Numbers JP17K19126,
JP16H04150 and JP15H05839 (Middle Molecular Strategy). T. K. is also grateful for support by
JSPS KAKENHI Grant Number JP18H04271 (Precisely Designed Catalysts with Customized
Scaffolding). H.K. is also grateful to the Japan Society for the Promotion of Science (JSPS) for a
Research Fellowship for Young Scienetists (JP16J02904).
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References and Notes
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Recent Progress in Nickel-Catalyzed Biaryl Coupling. Eur. J. Org. Chem. 2013, 2013, 19–30. (e)
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(3) Selected examples of C–H monofunctionalizations: (a) Oi, S.; Fukita, S.; Hirata, N.;
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