Nickel-Catalyzed Transformation of Aryl 2-Pyridyl Ethers via Cleavage of the Carbon-Oxygen Bond: Synthesis of Mono-α-arylated Ketones

Article abstract of DOI:10.1055/s-0037-1609963

The nickel/IPr-catalyzed reaction of aryl 2-pyridyl ethers with propiophenone and acetophenone derivatives via C-OPy bond cleavage is performed in the presence of t -BuOLi to give mono-α-arylated ketones in moderate yields. The method is suitable for electron-rich and electron-poor ethers as well as heteroaryl ethers and tolerates a range of active functional groups.

Full text of DOI:10.1055/s-0037-1609963

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2018, 50, A–G
special topic
A
en
J. Li, Z.-X. Wang
Special Topic
Synthesis
Nickel-Catalyzed Transformation of Aryl 2-Pyridyl Ethers via
Cleavage of the Carbon–Oxygen Bond: Synthesis of Mono-α-
arylated Ketones
Jing Lia
Zhong-Xia Wang*a,b
O
Ni(COD)2 (10 mol%)
IPr·HCl (20 mol%)
O
OPy
R1
0
0
0
0
0-
0
0
1
8-
1
2
6
8-
7
7
8
+
R
Ar
Ar
t-BuOLi (3.4 equiv)
1,4-dioxane
100 °C, 12 h
R
H
R1
a CAS Key Laboratory of Soft Matter Chemistry, Hefei National Laboratory
for Physical Sciences at Microscale and Department of Chemistry,
University of Science and Technology of China, Hefei, Anhui 230026,
P. R. of China
b Collaborative Innovation Center of Chemical Science and Engineering,
Tianjin 300072, P. R. of China
R
1 = Me, H
21 examples
up to 78% yield
zxwang@ustc.edu.cn
Published as part of the Special Topic Modern Coupling Approaches and
their Strategic Applications in Synthesis
Received: 17.02.2018
Accepted after revision: 13.04.2018
Published online: 29.05.2018
arylation reagents employed, aryl halides and sulfonates of
phenols were predominant.5d,6 More recently, aryl pivalates
were used in the α-arylation of ketones.7 It is therefore in-
teresting to explore transition-metal-catalyzed reactions of
aryl 2-pyridyl ethers with ketones to synthesize α-aryl ke-
tones.
DOI: 10.1055/s-0037-1609963; Art ID: ss-2018-c0096-st
Abstract The nickel/IPr-catalyzed reaction of aryl 2-pyridyl ethers with
propiophenone and acetophenone derivatives via C–OPy bond cleav-
age is performed in the presence of t-BuOLi to give mono-α-arylated
ketones in moderate yields. The method is suitable for electron-rich and
electron-poor ethers as well as heteroaryl ethers and tolerates a range
of active functional groups.
2-[4-(tert-Butyl)phenoxy]pyridine (1a) and propiophe-
none (2a) were chosen as the model substrates to screen
the reaction conditions (Table 1). We first tested the reac-
tion using a combination of Ni(COD)2 (10 mol%) and a N-
heterocyclic carbene (20 mol%) (IPr, IMes, SIPr, and ICy) as
the catalyst, t-BuOLi (1.2 equiv) as the base, and 1,4-diox-
ane as the solvent. The combination of Ni(COD)2 and IPr led
to the desired product in 39% yield after the reaction was
run at 120 °C for 12 hours, whilst the same reactions with
IMes, SIPr, and ICy were ineffective (Table 1, entries 1–4).
The combination of Ni(COD)2 and phosphine ligands includ-
ing dcype, BINAP, and PCy3 also proved to be ineffective (Ta-
ble 1, entries 5–7). Hence, we chose the Ni(COD)2/IPr com-
bination as the catalyst in subsequent reactions. We noticed
that a higher t-BuOLi loading (2.4 equiv) led to a higher
product yield (Table 1, entry 8). However, employing 2.4
equivalents of t-BuONa, NaHMDS, or LiHMDS resulted in a
lower product yield than when using 1.2 equivalents of the
corresponding base (Table 1, entries 9–14). This is probably
due to the excess strong base causing side reactions. t-
BuOK, MeOLi and Cs2CO3 were demonstrated to be ineffec-
tive in this reaction (Table 1, entries 15–17). The solvent ef-
fect was next studied with THF, n-Bu2O and toluene proving
to be less effective than 1,4-dioxane (Table 1, entries 18–
20). Both DMF and DMAc gave comparable results to 1,4-di-
oxane (Table 1, entries 21 and 22). However, we were un-
able to further improve the yield in DMAc via optimization
of the conditions (Table 1, entry 23). Increasing the propio-
phenone loading to 1.5 equivalents and the corresponding
amount of t-BuOLi resulted in increased yields (Table 1, en-
Key words aryl 2-pyridyl ethers, C–O activation, C–C coupling, nickel
catalyst, α-arylated ketones
Phenol and its derivatives are inexpensive and readily
available; hence, they are often used as starting materials in
organic synthesis. Among phenol-based transformations,
transition-metal-catalyzed cross-couplings via C–O bond
cleavage has attracted significant attention in recent years.1
A range of phenol-based electrophiles including aryl methyl
ethers, carboxylates, carbamates, carbonates, phosphora-
mides, phosphates, sulfamates, tosylates and mesylates
have been employed to construct new C–C, C–N and C–H
bonds.1 Recently, aryl 2-pyridyl ethers were demonstrated
to participate in catalytic coupling with appropriate nucleo-
philic reagents such as B2(pin)2 and amines, and to undergo
reduction to C–H via loss of the 2-pyridyloxy (OPy) group.2
Because the OPy group in aryl 2-pyridyl ether systems is an
effective directing group,3 these reactions also provide a
valuable method for subsequent conversion of the 2-pyr-
idyloxy directing group in C–H functionalization reactions.
On the other hand, the transition-metal-catalyzed α-
arylation of carbonyl compounds has attracted wide atten-
tion because α-aryl carbonyl compounds are common
structural motifs in pharmaceutical and other biologically
active molecules.4 A variety of effective catalytic systems
and arylation reagents have been developed.5 Among the
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–G

B
J. Li, Z.-X. Wang
Special Topic
Synthesis
tries 24 and 25). Reducing the amount of the Ni(COD)2 cata-
lyst to 5 mol% led to a decrease in the yield (Table 1, entry
26). We also found that the reaction at 100 °C gave the
same yield as that at 120 °C. However, further lowering the
reaction temperature led to a marked decline in the yield
(Table 1, entries 27 and 28).
With optimized conditions in hand (Table 1, entry 27),
we next tested the scope of the aryl 2-pyridyl ethers and
the results are listed in Table 2. Aryl 2-pyridyl ethers with
various substituents on the phenyl rings, including elec-
tron-donating and electron-withdrawing groups, reacted
smoothly with propiophenone to afford the corresponding
products in 34–76% yields. It appeared that the reaction re-
sults were not controlled by the electronic effect of the sub-
stituents. 2-(Naphthalen-2-yloxy)pyridine showed similar
reactivity to substituted phenyl 2-pyridyl ethers such as 2-
Table 1 Optimization of the Reaction Conditionsa
OPy
O
Ni(COD)2 (10 mol%)
ligand (20 mol%)
O
Ar
+
Ph
(4-methoxyphenoxy)pyridine
and
2-(4-phenoxyphe-
Ph
t-Bu
120 °C, 12 h
noxy)pyridine (Table 2, entries 2, 4 and 5). 6-(Pyridin-2-
yloxy)quinoline also reacted smoothly with propiophenone
to produce 1-phenyl-2-(quinolin-6-yl)propan-1-one in 44%
yield. No products formed via CPy–O cleavage were ob-
served. Among the aryl 2-pyridyl ethers, 2-[4-(trifluoro-
methyl)phenoxy]pyridine gave the lowest product yield
(Table 2, entry 9). This is ascribed to the existence of side
reactions, and we did observe a series of by-products via
TLC analysis. Common aryl, alkyl, alkoxy and amino groups
and active functional groups including F, CF3, PhC(O), t-
BuOC(O) and CN groups were tolerated. An acetyl group
was not tolerated due to the existence of active hydrogens.
However, 2-[4-(2-methyl-1,3-dioxolan-2-yl)phenoxy]pyri-
dine was able to undergo the reaction with propiophenone
to yield 2-[4-(2-methyl-1,3-dioxolan-2-yl)phenyl]-1-phen-
ylpropan-1-one (3d) (Table 2, entry 3). The 2-methyl-1,3-
dioxolan-2-yl group in the product can be readily converted
into an acetyl group via hydrolysis.
1a
2a
3a
Entry
Ligand
IPr·HCl
Base (equiv)
Solvent
Yield (%)b
1
2
t-BuOLi (1.2)
t-BuOLi (1.2)
t-BuOLi (1.2)
t-BuOLi (1.2)
t-BuOLi (1.2)
t-BuOLi (1.2)
t-BuOLi (1.2)
t-BuOLi (2.4)
t-BuONa (1.2)
t-BuONa (2.4)
NaHMDS (1.2)
NaHMDS (2.4)
LiHMDS (1.2)
LiHMDS (2.4)
t-BuOK (1.2)
MeOLi (1.2)
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
THF
39
IMes·HCl
SIPr·HCl
ICy·HCl
dcype
trace
trace
trace
trace
trace
trace
56
3
4
5
6
BINAP
7
PCy3
8
IPr·HCl
IPr·HCl
IPr·HCl
IPr·HCl
IPr·HCl
IPr·HCl
IPr·HCl
IPr·HCl
IPr·HCl
IPr·HCl
IPr·HCl
IPr·HCl
IPr·HCl
IPr·HCl
IPr·HCl
IPr·HCl
IPr·HCl
IPr·HCl
IPr·HCl
IPr·HCl
IPr·HCl
9
45
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
33
48
trace
60
Table 2 Scope of the Aryl 2-Pyridyl Ethersa
trace
–
Ni(COD)2 (10 mol%)
IPr•HCl (20 mol%)
O
O
–
Ar
ArOPy
+
Ph
Ph
Cs2CO3 (1.2)
t-BuOLi (1.2)
t-BuOLi (1.2)
t-BuOLi (1.2)
t-BuOLi (1.2)
t-BuOLi (1.2)
t-BuOLi (2.4)
t-BuOLi (1.5)
t-BuOLi (3.4)
t-BuOLi (3.4)
t-BuOLi (3.4)
t-BuOLi (3.4)
–
t-BuOLi (3.4 equiv)
1,4-dioxane, 100 °C, 12 h
1
2a
3b–n
20
n-Bu2O
24
Entry
1
Product
Yield (%)b
toluene
30
Ph
O
DMF
38
51
64
DMAc
43
Ph
DMAc
43c
59c
3b
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
O
78c
2
3
64c,d
78c,e (77f)
52c,g
Ph
3c
O
a Unless otherwise specified, the reactions were performed with 2-[4-(tert-
butyl)phenoxy]pyridine (1a) (0.2 mmol) and propiophenone (2) (1.2 equiv)
according to the conditions indicated in the above scheme.
b NMR yield.
O
O
54
Ph
c Propiophenone (1.5 equiv) of was employed.
d Ni(COD)2 (5 mol%) was employed.
3d
e The reaction was run at 100 °C.
f Yield of isolated product.
g The reaction was run at 80 °C.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–G

C
J. Li, Z.-X. Wang
Special Topic
Synthesis
Table 2 (continued)
Next, we examined the scope of the ketones and the re-
sults are listed in Table 3. 1-(4-Fluorophenyl)propan-1-one
reacted smoothly with para-tert-butyl-, para-methoxy-,
and para-fluoro-substituted phenyl 2-pyridyl ethers, re-
spectively, to afford the corresponding products in 47–59%
yields (Table 3, entries 1–3).
Entry
Product
Yield (%)b
64
MeO
O
4
Ph
Compared with propiophenone, 1-(4-fluorophenyl)pro-
pan-1-one exhibited lower reactivity. It was expected that
ketones with an electron-rich aryl group such as 1-(4-me-
thoxyphenyl)propan-1-one would give better results. How-
ever, the reaction of 1-(4-methoxyphenyl)propan-1-one
with each of the above ethers led to a mixture of products
for reasons that are unclear.
3e
PhO
O
5
6
7
65
47
49
Ph
3f
O
O
O
It was previously reported that the catalytic α-arylation
of acetophenones often results in polyarylations or aldol
condensations as major side reactions.8 Our catalyst system
was demonstrated to drive only mono-α-arylation of ace-
tophenone derivatives. The tested nucleophilic substrates
included acetophenone, 1-(4-methoxyphenyl)ethan-1-one,
and 1-(naphthalen-2-yl)ethan-1-one. The ethers used in
the test included 2-(4-methoxyphenoxy)pyridine and 2-(o-
tolyloxy)pyridine. 1-(4-Methoxyphenyl)ethan-1-one showed
higher reactivity when it reacted with 2-(4-methoxyphe-
noxy)pyridine (Table 3, entries 4 and 5). 1-(Naphthalen-2-
yl)ethan-1-one exhibited similar reactivity to acetophe-
none (Table 3, entry 7). The reaction of 2-(o-tolyloxy)pyri-
dine with acetophenone gave the desired product in only
29% yield (Table 3, entry 6). This might be due to steric hin-
drance from the o-methyl group in 2-(o-tolyloxy)pyridine.
This phenomenon is also consistent with the reaction of ar-
yltrimethylammonium triflates with acetophenone.5e
In summary, we have developed a nickel catalyst system
to realize the functionalization of aryl 2-pyridyl ethers via
CAr–OPy bond cleavage. A series of α-arylated ketones was
synthesized in moderate yields through this reaction. The
method shows a broad scope of aryl 2-pyridyl ethers, in-
cluding electron-rich and electron-poor ethers as well as
heteroaryl ethers. Propiophenone, acetophenone deriva-
tives and 1-(naphthalen-2-yl)ethanone can be employed as
substrates, resulting in only mono-α-arylated products.
Various reactive functional groups such as fluoro, trifluoro-
methyl, benzoyl, tert-butoxycarbonyl, cyano and the β-H of
the ketones were tolerated. We believe that this methodolo-
gy provides a valuable complement to the current proce-
dures for the α-arylation of ketones and should enrich the
utilization of phenolic derivatives in synthetic chemistry.
Ph
3g
O
Me2N
Ph
3h
F
O
8
9
76
34
Ph
3i
F3C
O
Ph
3j
O
Ph
O
10
11
46
51
Ph
3k
O
t-BuO
O
Ph
3l
NC
O
12
13
46
44
Ph
3m
N
O
All reactions were performed under a nitrogen atmosphere using
standard Schlenk and vacuum line techniques. Toluene and THF were
purified using JC Meyer Phoenix Solvent Systems equipment. 1,4-Di-
oxane was distilled under nitrogen over sodium and degassed prior to
use. DMF and DMAc were dried over 4 Å molecular sieves, fractionally
distilled under reduced pressure and stored under nitrogen. Ni(COD)2
Ph
3n
a The reactions were performed with aryl 2-pyridyl ether 1 (0.2 mmol) and
propiophenone (2a) (1.5 equiv) according to the conditions indicated in
the above scheme.
b Yield of isolated product.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–G

D
J. Li, Z.-X. Wang
Special Topic
Synthesis
Table 3 Scope of the Ketonesa
using silica gel (Yantai Chemical Industry Research Institute, 200–300
mesh) with the eluent specified in each case. NMR spectra were re-
corded on a Bruker Avance III 400 spectrometer at ambient tempera-
ture. The 1H NMR chemical shifts are referenced to TMS and the 13C
NMR chemical shifts are referenced to the internal solvent resonanc-
es. The 19F NMR chemical shifts are referenced to external CF3COOH.
High-resolution mass spectra (HRMS) were acquired on a Waters G2
XS-QTof mass spectrometer.
Ni(COD)2 (10 mol%)
IPr•HCl (20 mol%)
O
OPy
O
R1
+
R
Ar
R
Ar
t-BuOLi (3.4 equiv)
R1
4/5
1,4-dioxane, 100 °C, 12 h
1
2
Entry
1
Product
Yield (%)b
2-[4-(tert-Butyl)phenyl]-1-phenylpropan-1-one (3a);10 Typical
Procedure
t-Bu
O
A Schlenk tube was charged with Ni(COD)2 (5.5 mg, 0.02 mmol), IP-
r·HCl (17 mg, 0.04 mmol), t-BuOLi (55 mg, 0.68 mmol), 2-[4-(tert-bu-
tyl)phenoxy]pyridine (45.4 mg, 0.2 mmol), propiophenone (2a) (40.2
mg, 0.3 mmol), and 1,4-dioxane (2 mL). The mixture was stirred at
100 °C for 12 h. The volatiles were removed by rotary evaporation.
The residue was purified by column chromatography on silica gel to
afford 2-[4-(tert-butyl)phenyl]-1-phenyl propan-1-one (3a).
59
F
4a
MeO
O
2
3
4
47
48
58
White solid; yield: 41.6 mg (78%); eluent: petroleum ehter/EtOAc,
100:1 (v/v).
1H NMR (400 MHz, CDCl3): δ = 7.90 (d, J = 7.4 Hz, 2 H), 7.40 (t, J = 7.3
Hz, 1 H), 7.30 (t, J = 7.6 Hz, 2 H), 7.22 (d, J = 8.3 Hz, 2 H), 7.14 (d, J = 8.3
Hz, 2 H), 4.60 (q, J = 6.8 Hz, 1 H), 1.44 (d, J = 6.9 Hz, 3 H), 1.19 (s, 9 H).
13C NMR (101 MHz, CDCl3): δ = 200.66, 149.78, 138.32, 136.66,
132.87, 128.94, 128.60, 127.49, 125.99, 47.33, 34.52, 31.43, 19.64.
F
4b
F
O
F
4c
2-([1,1′-Biphenyl]-4-yl)-1-phenylpropan-1-one (3b)11
MeO
O
White solid; yield: 29.2 mg (51%); eluent: toluene.
1H NMR (400 MHz, CDCl3): δ = 7.99 (d, J = 8.5 Hz, 2 H), 7.59–7.46 (m, 5
H), 7.45–7.28 (m, 7 H), 4.74 (q, J = 6.8 Hz, 1 H), 1.58 (d, J = 6.8 Hz, 3 H).
OMe
13C NMR (101 MHz, CDCl3): δ = 200.41, 140.73, 140.56, 139.92,
136.56, 132.99, 128.92, 128.85, 128.65, 128.30, 127.81, 127.37,
127.11, 47.58, 19.62.
5a
MeO
O
5
6
7
47
2-(Naphthalen-2-yl)-1-phenylpropan-1-one (3c)11
White solid; yield: 33.3 mg (64%); eluent: toluene.
5b
1H NMR (400 MHz, CDCl3): δ = 7.98 (d, J = 7.3 Hz, 2 H), 7.77 (t, J = 7.8
Hz, 3 H), 7.72 (s, 1 H), 7.51–7.38 (m, 4 H), 7.35 (t, J = 7.6 Hz, 2 H), 4.84
(q, J = 6.8 Hz, 1 H), 1.61 (d, J = 6.8 Hz, 3 H).
13C NMR (101 MHz, CDCl3): δ = 200.41, 139.12, 136.55, 133.78,
132.95, 132.47, 128.93, 128.62, 127.84, 127.74, 126.54, 126.30,
126.06, 125.91, 48.16, 19.66.
O
29c
5c
MeO
O
2-[4-(2-Methyl-1,3-dioxolan-2-yl)phenyl)]-1-phenylpropan-1-one
(3d)
48c
Colorless oil; yield: 32.0 mg (54%); eluent: petroleum ether/EtOAc,
15:1 (v/v).
5d
a The reactions were performed with aryl 2-pyridyl ether 1 (0.2 mmol) and
ketone 2 (1.5 equiv) according to the conditions indicated in the above
1H NMR (400 MHz, CDCl3): δ = 7.97 (d, J = 7.2 Hz, 2 H), 7.49 (t, J = 6.8
Hz, 1 H), 7.43–7.36 (m, 4 H), 7.26 (d, J = 8.4 Hz, 2 H), 4.71 (q, J = 6.9 Hz,
1 H), 4.05–3.95 (m, 2 H), 3.80–3.70 (m, 2 H), 1.61 (s, 3 H), 1.53 (d, J =
6.9 Hz, 3 H).
scheme.
b Yield of isolated product.
c NMR yield.
13C NMR (101 MHz, CDCl3): δ = 200.42, 142.07, 140.97, 136.54,
132.97, 128.92, 128.63, 127.71, 125.98, 108.80, 64.58, 64.56, 47.45,
27.60, 19.63.
HRMS (ESI): m/z [M + H]+ calcd for C19H21O3: 297.1491; found:
297.1492.
was purchased from Alfa Aesar. NHC ligand precursors9 and aryl 2-
pyridyl ethers2a,b were prepared according to reported procedures.
CDCl3 was purchased from Cambridge Isotope Laboratories and used
as received. All other chemicals were obtained from commercial ven-
dors and used as received. Column chromatography was performed
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–G

E
J. Li, Z.-X. Wang
Special Topic
Synthesis
2-(4-Methoxyphenyl)-1-phenylpropan-1-one (3e)11
1H NMR (400 MHz, CDCl3): δ = 7.99–7.91 (m, 2 H), 7.56 (d, J = 8.0 Hz, 2
H), 7.51 (t, J = 7.4 Hz, 1 H), 7.46–7.36 (m, 4 H), 4.77 (q, J = 6.9 Hz, 1 H),
1.56 (d, J = 6.9 Hz, 3 H).
White solid; yield: 30.8 mg (64%); eluent: petroleum ether/EtOAc,
20:1 (v/v).
13C NMR (101 MHz, CDCl3): δ = 199.77, 145.49, 136.21, 133.32, 129.37
(q, J = 32.5 Hz), 128.85, 128.81, 128.30, 126.05 (q, J = 3.7 Hz), 124.20
(q, J = 273.0 Hz), 47.63, 19.56.
1H NMR (400 MHz, CDCl3): δ = 7.98–7.92 (m, 2 H), 7.47 (t, J = 7.4 Hz, 1
H), 7.38 (t, J = 7.5 Hz, 2 H), 7.20 (d, J = 8.7 Hz, 2 H), 6.83 (d, J = 8.8 Hz, 2
H), 4.64 (q, J = 6.8 Hz, 1 H), 3.75 (s, 3 H), 1.51 (d, J = 6.9 Hz, 3 H).
13C NMR (101 MHz, CDCl3): δ = 200.68, 158.60, 136.64, 133.62,
132.85, 128.92, 128.89, 128.60, 114.51, 55.35, 47.11, 19.66.
2-(4-Benzoylphenyl)-1-phenylpropan-1-one (3k)6a
White solid; yield: 28.9 mg (46%); eluent: petroleum ether/EtOAc,
10:1 (v/v).
1H NMR (400 MHz, CDCl3): δ = 8.00–7.93 (m, 2 H), 7.79–7.72 (m, 4 H),
7.57 (t, J = 7.4 Hz, 1 H), 7.51 (t, J = 7.4 Hz, 1 H), 7.49–7.36 (m, 6 H), 4.79
(q, J = 6.8 Hz, 1 H), 1.58 (d, J = 6.9 Hz, 3 H).
13C NMR (101 MHz, CDCl3): δ = 199.81, 196.35, 146.27, 137.63,
136.36, 136.33, 133.25, 132.54, 130.98, 130.11, 128.89, 128.77,
128.40, 127.90, 47.90, 19.51.
2-(4-Phenoxyphenyl)-1-phenylpropan-1-one (3f)
White solid; yield: 39.3 mg (65%); eluent: petroleum ether/EtOAc,
20:1 (v/v).
1H NMR (400 MHz, CDCl3): δ = 7.96 (d, J = 7.4 Hz, 2 H), 7.49 (t, J = 7.4
Hz, 1 H), 7.40 (t, J = 7.6 Hz, 2 H), 7.35–7.27 (m, 2 H), 7.24 (d, J = 8.6 Hz,
2 H), 7.08 (t, J = 7.4 Hz, 1 H), 6.97 (d, J = 7.6 Hz, 2 H), 6.92 (d, J = 8.8 Hz,
2 H), 4.68 (q, J = 6.9 Hz, 1 H), 1.53 (d, J = 6.9 Hz, 3 H).
13C NMR (101 MHz, CDCl3): δ = 200.51, 157.06, 156.34, 136.53,
136.17, 132.98, 129.85, 129.19, 128.89, 128.65, 123.47, 119.21,
119.13, 47.10, 19.68.
HRMS (ESI): m/z [M + H]+ calcd for C21H19O2: 303.1385; found:
303.1383.
tert-Butyl 4-(1-Oxo-1-phenylpropan-2-yl)benzoate (3l)
White solid; yield: 31.6 mg (51%); eluent: petroleum ether/EtOAc,
15:1 (v/v).
1H NMR (400 MHz, CDCl3): δ = 7.95–7.89 (m, 4 H), 7.48 (t, J = 7.4 Hz, 1
H), 7.37 (t, J = 7.6 Hz, 2 H), 7.33 (d, J = 8.4 Hz, 2 H), 4.73 (q, J = 6.8 Hz, 1
H), 1.56 (s, 9 H), 1.54 (d, J = 7.2 Hz, 3 H).
13C NMR (101 MHz, CDCl3): δ = 199.83, 165.57, 146.24, 136.33,
133.12, 130.85, 130.28, 128.86, 128.69, 127.77, 81.11, 48.03, 28.28,
19.44.
2-(Benzo[d][1,3]dioxol-5-yl)-1-phenylpropan-1-one (3g)12
White solid; yield: 23.9 mg (47%); eluent: petroleum ether/EtOAc,
15:1 (v/v).
1H NMR (400 MHz, CDCl3): δ = 8.00–7.91 (m, 2 H), 7.48 (t, J = 8.0 Hz, 1
H), 7.39 (t, J = 7.5 Hz, 2 H), 6.81–6.68 (m, 3 H), 5.89 (dd, J = 6.5, 1.4 Hz,
2 H), 4.60 (q, J = 6.8 Hz, 1 H), 1.49 (d, J = 6.9 Hz, 3 H).
HRMS (ESI): m/z [M + H]+ calcd for C20H23O3: 311.1647; found:
311.1639.
13C NMR (101 MHz, CDCl3): δ = 200.34, 148.15, 146.61, 136.53,
135.32, 132.93, 128.86, 128.62, 128.58, 121.13, 108.78, 108.21,
101.14, 47.52, 19.66.
4-(1-Oxo-1-phenylpropan-2-yl)benzonitrile (3m)13
Colorless oil; yield: 21.6 mg (46%); eluent: petroleum ether/EtOAc,
15:1 (v/v).
2-(3-(Dimethylamino)phenyl)-1-phenylpropan-1-one (3h)6a
1H NMR (400 MHz, CDCl3): δ = 7.97–7.88 (m, 2 H), 7.60 (d, J = 8.4 Hz, 2
H), 7.53 (t, J = 7.4 Hz, 1 H), 7.46–7.37 (m, 4 H), 4.77 (q, J = 6.9 Hz, 1 H),
1.56 (d, J = 6.9 Hz, 3 H).
13C NMR (101 MHz, CDCl3): δ = 199.36, 146.77, 136.02, 133.48,
132.87, 128.86, 128.79, 118.78, 111.06, 47.74, 19.43.
Colorless oil; yield: 24.8 mg (49%); eluent: petroleum ether/EtOAc,
10:1 (v/v).
1H NMR (400 MHz, CDCl3): δ = 8.00–7.94 (m, 2 H), 7.45 (t, J = 7.4 Hz, 1
H), 7.36 (t, J = 7.5 Hz, 2 H), 7.15 (t, J = 7.9 Hz, 1 H), 6.64 (d, J = 7.6 Hz, 1
H), 6.61–6.54 (m, 2 H), 4.61 (q, J = 6.8 Hz, 1 H), 2.90 (s, 6 H), 1.53 (d, J =
6.8 Hz, 3 H).
1-Phenyl-2-(quinolin-6-yl)propan-1-one (3n)14
13C NMR (101 MHz, CDCl3): δ = 200.63, 151.10, 142.52, 136.82,
132.73, 129.75, 128.89, 128.52, 116.22, 111.62, 111.18, 48.60, 40.65,
19.67.
Light yellow oil; yield: 23.0 mg (44%); eluent: petroleum ether/EtOAc,
2:1 (v/v).
1H NMR (400 MHz, CDCl3): δ = 8.86 (dd, J = 4.2, 1.7 Hz, 1 H), 8.11–8.04
(m, 2 H), 8.02–7.95 (m, 2 H), 7.73–7.67 (m, 2 H), 7.47 (t, J = 6.7 Hz, 1
H), 7.42–7.32 (m, 3 H), 4.90 (q, J = 6.9 Hz, 1 H), 1.63 (d, J = 6.9 Hz, 3 H).
2-(4-Fluorophenyl)-1-phenylpropan-1-one (3i)11
13C NMR (101 MHz, CDCl3): δ = 200.13, 150.43, 147.44, 139.90,
136.34, 136.01, 133.14, 130.35, 129.90, 128.88, 128.71, 128.56,
126.23, 121.45, 47.75, 19.66.
Colorless oil; yield: 34.7 mg (76%); eluent: toluene.
1H NMR (400 MHz, CDCl3): δ = 7.99–7.90 (m, 2 H), 7.49 (t, J = 7.4 Hz, 1
H), 7.39 (t, J = 7.6 Hz, 2 H), 7.30–7.20 (m, 2 H), 6.97 (t, J = 8.7 Hz, 2 H),
4.69 (q, J = 6.9 Hz, 1 H), 1.51 (d, J = 6.9 Hz, 3 H).
2-[4-(tert-Butyl)phenyl]-1-(4-fluorophenyl)propan-1-one (4a)
13C NMR (101 MHz, CDCl3): δ = 200.35, 161.87 (d, J = 245.4 Hz),
137.21 (d, J = 6.4 Hz), 136.38, 133.06, 129.41 (d, J = 8.0 Hz), 128.83,
128.67, 115.93 (d, J = 21.5 Hz), 47.03, 19.67.
Colorless oil; yield: 33.5 mg (59%); eluent: toluene.
1H NMR (400 MHz, CDCl3): δ = 7.99 (dd, J = 8.9, 5.5 Hz, 2 H), 7.30 (d,
J = 8.4 Hz, 2 H), 7.19 (d, J = 8.4 Hz, 2 H), 7.04 (t, J = 8.6 Hz, 2 H), 4.62 (q,
J = 6.8 Hz, 1 H), 1.51 (d, J = 6.8 Hz, 3 H), 1.27 (s, 9 H).
19F NMR (376 MHz, CDCl3): δ = –115.79.
1-Phenyl-2-[4-(trifluoromethyl)phenyl]propan-1-one (3j)6a
13C NMR (101 MHz, CDCl3): δ = 199.04, 165.56 (d, J = 255.3 Hz),
149.93, 138.21, 133.01 (d, J = 3.0 Hz), 131.56 (d, J = 9.3 Hz), 127.40,
126.08, 115.68 (d, J = 21.8 Hz), 47.46, 34.53, 31.42, 19.61.
Colorless oil; yield: 18.9 mg (34%); eluent: toluene.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–G

F
J. Li, Z.-X. Wang
Special Topic
Synthesis
HRMS (ESI): m/z [M + H]+ calcd for C19H22OF: 285.1655; found:
285.1651.
References
(1) (a) Rosen, B. M.; Quasdorf, K. W.; Wilson, D. A.; Zhang, N.;
Resmerita, A.-M.; Garg, N. K.; Percec, V. Chem. Rev. 2011, 111,
1346. (b) Mesganaw, T.; Garg, N. K. Org. Process Res. Dev. 2013,
17, 29. (c) Gooßen, L. J.; Gooßen, K.; Stanciu, C. Angew. Chem. Int.
Ed. 2009, 48, 3569. (d) Li, B.-J.; Yu, D.-G.; Sun, C.-L.; Shi, Z.-J.
Chem. Eur. J. 2011, 17, 1728. (e) Han, F.-S. Chem. Soc. Rev. 2013,
42, 5270.
(2) (a) Kinuta, H.; Tobisu, M.; Chatani, N. J. Am. Chem. Soc. 2015,
137, 1593. (b) Tobisu, M.; Zhao, J.; Kinuta, H.; Furukawa, T.;
Igarashi, T.; Chatani, N. Adv. Synth. Catal. 2016, 358, 2417. (c) Li,
J.; Wang, Z.-X. Org. Lett. 2017, 19, 3723. (d) Li, J.; Wang, Z.-X.
Chem. Commun. 2018, 54, 2138.
1-(4-Fluorophenyl)-2-(4-methoxyphenyl)propan-1-one (4b)6f
Colorless oil; yield: 24.3 mg (47%); eluent: petroleum ether/EtOAc,
20:1 (v/v).
1H NMR (400 MHz, CDCl3): δ = 7.97 (dd, J = 7.8, 4.4 Hz, 2 H), 7.18 (d,
J = 8.7 Hz, 2 H), 7.04 (t, J = 8.6 Hz, 2 H), 6.83 (d, J = 8.7 Hz, 2 H), 4.58 (q,
J = 6.8 Hz, 1 H), 3.75 (s, 3 H), 1.49 (d, J = 6.8 Hz, 3 H).
13C NMR (101 MHz, CDCl3): δ = 199.05, 165.51 (d, J = 255.4 Hz),
158.65, 133.45, 132.93 (d, J = 2.9 Hz), 131.50 (d, J = 9.3 Hz), 128.83,
115.67 (d, J = 21.8 Hz), 114.57, 55.33, 47.19, 19.63.
19F NMR (376 MHz, CDCl3): δ = –105.70.
(3) (a) Kakiuchi, F.; Igi, K.; Matsumoto, M.; Hayamizu, T.; Chatani,
N.; Murai, S. Chem. Lett. 2002, 31, 396. (b) Ackermann, L.; Diers,
E.; Manvar, A. Org. Lett. 2012, 14, 1154. (c) Niu, L.; Yang, H.;
Wang, R.; Fu, H. Org. Lett. 2012, 14, 2618. (d) Yao, J.; Feng, R.;
Wu, Z.; Liu, Z.; Zhang, Y. Adv. Synth. Catal. 2013, 355, 1517.
(e) Liang, Y.-F.; Li, X.; Wang, X.; Yan, Y.; Feng, P.; Jiao, N. ACS
Catal. 2015, 5, 1956. (f) Lou, S.-J.; Chen, Q.; Wang, Y.-F.; Xu, D.-
Q.; Du, X.-H.; He, J.-Q.; Mao, Y.-J.; Xu, Z.-Y. ACS Catal. 2015, 5,
2846. (g) Chu, J.-H.; Lin, P.-S.; Wu, M.-J. Organometallics 2010,
29, 4058.
(4) (a) Wright, W. B. Jr.; Press, J. B.; Chan, P. S.; Marsico, J. W.; Haug,
M. F.; Lucas, J.; Tauber, J.; Tomcufcik, A. S. J. Med. Chem. 1986, 29,
523. (b) Goehring, R. R.; Sachdeva, Y. P.; Pisipati, J. S.; Sleevi, M.
C.; Wolfe, J. F. J. Am. Chem. Soc. 1985, 107, 435. (c) Venkatesan,
H.; Davis, M. C.; Altas, Y.; Snyder, J. P.; Liotta, D. C. J. Org. Chem.
2001, 66, 3653. (d) Johansson, C. C. C.; Colacot, T. J. Angew.
Chem. Int. Ed. 2010, 49, 676.
(5) (a) Satoh, T.; Kawamura, Y.; Miura, M.; Nomura, M. Angew.
Chem. Int. Ed. 1997, 36, 1740. (b) Palucki, M.; Buchwald, S. L.
J. Am. Chem. Soc. 1997, 119, 11108. (c) Hamann, B. C.; Hartwig, J.
F. J. Am. Chem. Soc. 1997, 119, 12382. (d) Bellina, F.; Rossi, R.
Chem. Rev. 2010, 110, 1082. (e) Li, J.; Wang, Z.-X. Org. Biomol.
Chem. 2016, 14, 7579.
(6) (a) Marelli, E.; Davies, M.; Nolan, S. P. Chem. Eur. J. 2014, 20,
17272. (b) Viciu, M. S.; Germaneau, R. F.; Nolan, S. P. Org. Lett.
2002, 4, 4053. (c) Liao, X.; Weng, Z.; Hartwig, J. F. J. Am. Chem.
Soc. 2008, 130, 195. (d) Nguyen, H. N.; Huang, X.; Buchwald, S. L.
J. Am. Chem. Soc. 2003, 125, 11818. (e) Hesp, K. D.; Lundgren, R.
J.; Stradiotto, M. J. Am. Chem. Soc. 2011, 133, 5194.
(f) Ackermann, L.; Mehta, V. P. Chem. Eur. J. 2012, 18, 10230.
(g) Alsabeh, P. G.; Stradiotto, M. Angew. Chem. Int. Ed. 2013, 52,
7242.
1,2-Bis(4-fluorophenyl)propan-1-one (4c)15
Colorless oil; yield: 23.6 mg (48%); eluent: toluene.
1H NMR (400 MHz, CDCl3): δ = 7.96 (dd, J = 8.9, 5.4 Hz, 2 H), 7.23 (dd,
J = 8.7, 5.3 Hz, 2 H), 7.06 (t, J = 8.7 Hz, 2 H), 6.99 (t, J = 8.8 Hz, 2 H), 4.63
(q, J = 6.9 Hz, 1 H), 1.51 (d, J = 6.9 Hz, 3 H).
13C NMR (101 MHz, CDCl3): δ = 198.73, 165.67 (d, J = 256.0 Hz),
161.95 (d, J = 246.8 Hz), 137.11 (d, J = 3.3 Hz), 132.75 (d, J = 3.0 Hz),
131.50 (d, J = 9.3 Hz), 129.35 (d, J = 8.1 Hz), 116.07 (d, J = 21.5 Hz),
115.82 (d, J = 21.9 Hz), 47.16, 19.70.
1,2-Bis(4-methoxyphenyl)ethan-1-one (5a)16
White solid; yield: 29.7 mg (58%); eluent: petroleum ether/EtOAc,
10:1 (v/v).
1H NMR (400 MHz, CDCl3): δ = 7.99 (d, J = 8.9 Hz, 2 H), 7.18 (d, J = 8.6
Hz, 2 H), 6.92 (d, J = 8.9 Hz, 2 H), 6.86 (d, J = 8.7 Hz, 2 H), 4.17 (s, 2 H),
3.85 (s, 3 H), 3.78 (s, 3 H).
13C NMR (101 MHz, CDCl3): δ = 196.68, 163.58, 158.56, 131.05,
130.50, 129.73, 127.05, 114.22, 113.88, 55.59, 55.36, 44.50.
2-(4-Methoxyphenyl)-1-phenylethan-1-one (5b)17
Colorless oil; yield: 21.2 mg (47%); eluent: petroleum ether/EtOAc,
15:1 (v/v).
1H NMR (400 MHz, CDCl3): δ = 8.04–7.98 (m, 2 H), 7.56 (t, J = 7.4 Hz, 1
H), 7.46 (t, J = 7.5 Hz, 2 H), 7.19 (d, J = 8.8 Hz, 2 H), 6.87 (d, J = 8.7 Hz, 2
H), 4.23 (s, 2 H), 3.79 (s, 3 H).
13C NMR (101 MHz, CDCl3): δ = 198.11, 158.89, 136.74, 133.18,
130.60, 128.83, 126.72, 114.28, 100.13, 55.40, 44.73.
(7) (a) Takise, R.; Muto, K.; Yamaguchi, J.; Itami, K. Angew. Chem. Int.
Ed. 2014, 53, 6791. (b) Cornella, J.; Jackson, E. P.; Martin, R.
Angew. Chem. Int. Ed. 2015, 54, 4075.
Funding Information
(8) (a) Matsubara, K.; Ueno, K.; Koga, Y.; Hara, K. J. Org. Chem. 2007,
72, 5069. (b) Fernández-Salas, J. A.; Marelli, E.; Cordes, D. B.;
Slawin, A. M. Z.; Nolan, S. P. Chem. Eur. J. 2015, 21, 3906.
(c) Henrion, M.; Chetcuti, M. J.; Ritleng, V. Chem. Commun. 2014,
50, 4624. (d) Grigalunas, M.; Ankner, T.; Norrby, P.-O.; Wiest, O.;
Helquist, P. J. Am. Chem. Soc. 2015, 137, 7019.
This work was supported by the National Natural Science Foundation
of China (grant no. 21172208) and the National Basic Research Pro-
gram of China (grant no. 2015CB856600).
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Supporting Information
(9) Fujimoto, T.; Ritter, T. Org. Lett. 2015, 17, 544.
(10) Grasa, G. A.; Colacot, T. J. Org. Lett. 2007, 9, 5489.
(11) Drapeau, M. P.; Fabre, I.; Grimaud, L.; Ciofini, I.; Ollevier, T.;
Taillefer, M. Angew. Chem. Int. Ed. 2015, 54, 10587.
Supporting information for this article is available online at
https://doi.org/10.1055/s-0037-1609963.
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(12) Hong, Y.-T.; Barchuk, A.; Krische, M. J. Angew. Chem. Int. Ed.
2006, 45, 6885.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–G

G
J. Li, Z.-X. Wang
Special Topic
Synthesis
(13) Mendoza-Espinosa, D.; González-Olvera, R.; Negrón-Silva, G. E.;
Angeles-Beltrán, D.; Suárez-Castillo, O. R.; Álvarez-Hernández,
A.; Santillan, R. Organometallics 2015, 34, 4529.
(14) Marelli, E.; Renault, Y.; Sharma, S. V.; Nolan, S. P.; Goss, R. J. M.
Chem. Eur. J. 2017, 23, 3832.
(15) Deng, Z.; Chen, C.; Cui, S. RSC Adv. 2016, 6, 93753.
(16) Speckmeier, E.; Padié, C.; Zeitler, K. Org. Lett. 2015, 17, 4818.
(17) Purohit, V. C.; Allwein, S. P.; Bakale, R. P. Org. Lett. 2013, 15,
1650.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–G