N-heterocyclic carbene-palladium(II)-1-methylimidazole complex catalyzed α-arylation of ketones with aryl chlorides

Article abstract of DOI:10.1055/s-0031-1289698

An easily available NHC-Pd(II)-Im (NHC=N-heterocyclic carbene, Im=1-methylimidazole) complex was found to be an efficient catalyst for the α-arylation reaction between ketones and aryl chlorides. Under the optimal conditions, all reactions proceeded smoot

Full text of DOI:10.1055/s-0031-1289698

PAPER
711
N-Heterocyclic Carbene–Palladium(II)–1-Methylimidazole Complex
Catalyzed a-Arylation of Ketones with Aryl Chlorides
Zheng-Kang Xiao, Li-Xiong Shao*
College of Chemistry and Materials Engineering, Wenzhou University, Chashan University Town, Wenzhou, Zhejiang Province 325035,
P. R. of China
Fax +86(577)86689300; E-mail: Shaolix@wzu.edu.cn
Received 12 November 2011; revised 6 January 2012
wish to report its application in the a-arylation reaction
Abstract: An easily available NHC–Pd(II)–Im (NHC = N-hetero-
between ketones and aryl chlorides under mild conditions.
cyclic carbene, Im = 1-methylimidazole) complex was found to be
an efficient catalyst for the a-arylation reaction between ketones
and aryl chlorides. Under the optimal conditions, all reactions pro-
ceeded smoothly to give the desired products in good to high yields
within hours.
Initial examinations were carried out using 4-methox-
yphenyl chloride (2a, 1.0 equiv) and 1-phenylpropan-1-
one (3a, 1.0 mmol) as the substrates, and NHC–Pd(II)–Im
complex 1 (1.0 mol%) as the catalyst, in tetrahydrofuran
(1.0 mL) at 80 °C for 24 hours to establish the best base
(Table 1, entries 1–6). It was found that potassium tert-
butoxide was the most suitable, and the corresponding a-
arylation product 4a was obtained in 68% yield (Table 1,
entry 1). Different neutral and polar solvents were also
tested (Table 1, entries 7–10) and, to our pleasure, the
yield could be further increased to 78% with N,N-dimeth-
ylformamide as the solvent (Table 1, entry 10). Finally, an
important change in the ratio of 2a to 3a (1.2:1) was found
to be favorable, and product 4a was achieved in 90% yield
within three hours in N,N-dimethylformamide (Table 1,
entry 11).
Key words: N-heterocyclic carbenes, palladium, a-arylation, aryl
chlorides, ketones
Palladium-catalyzed cross-coupling reactions, for which
the 2010 Nobel Prize in chemistry was awarded, have
been shown to be versatile methods for the formation of
carbon–carbon and carbon–heteroatom bonds.1 Among
them, since its initial investigations,2 the palladium-cata-
lyzed a-arylation of carbonyl compounds has become a
powerful new method for the formation of carbon–carbon
bonds.3 In most cases, great attention was paid to the hin-
dered monodentate phosphine ligands in order to improve
the efficiency of this reaction. It should be noted here that
phosphine-based ligands are expensive and are labile to-
ward oxidation. Consequently, it is necessary to develop
air-stable and low-cost ligands to facilitate the palladium-
catalyzed a-arylation reactions. During the past years, N-
heterocyclic carbene (NHC)–palladium complexes,4 usu-
ally with higher air, moisture and thermal stability than
phosphine–palladium complexes, have shown good cata-
lytic activity in the a-arylation of ketones;5,6 however, the
efficient NHC–palladium complexes reported to date
have some obvious drawbacks. For example, expensive
palladium complex precursors and/or lengthy procedures
are involved. Thus, there is still a great demand to develop
easily available and less expensive NHC–palladium com-
plexes for the a-arylation of ketones. Recently, we have
developed a new, well-defined NHC–Pd(II)–Im (Im = 1-
methylimidazole) complex 1 (Figure 1), which can be
easily synthesized from commercially available IPr·HCl,
PdCl2 and 1-methylimidazole in a one-step procedure in
high yield, and have found it to be an efficient catalyst in
amination reactions, the Suzuki–Miyaura coupling reac-
tion and the Hiyama reaction with aryl chlorides as the
substrates.7 These results prompted us to investigate other
applications of complex 1 in organic synthesis. Herein, we
i-Pr
i-Pr
Cl
Me
N
N
Pd
Cl
N
N
i-Pr
i-Pr
Figure 1 NHC–Pd(II)–Im complex 1
The optimized reaction conditions were then applied to a
variety of aryl chlorides 2 and ketones 3 to investigate the
generality of the reaction. As can be seen from Table 2,
the solvents used influence the reactions to some extent.
For example, for the reactions shown in entries 1–6 and
10, better results were obtained with N,N-dimethylform-
amide as the solvent, while for the reactions shown in en-
tries 7–9 and 11–13, better results were achieved when the
corresponding reactions were carried out in toluene. In ad-
dition, for the reaction between 4-methoxyphenyl chlo-
ride (2a) and acetophenone (3e), tetrahydrofuran was
found to be the best solvent, giving a higher yield than the
reaction in N,N-dimethylformamide or in toluene
(Table 2, entry 14). At this stage, the mechanism of this
solvent effect is still unclear. In the appropriate solvents,
all reactions worked well to give the corresponding a-ary-
lated products 4 in moderate to high yields. Substituents
SYNTHESIS 2012, 44, 711–716
x
x
.x
x
.2
0
1
2
Advanced online publication: 10.02.2012
DOI: 10.1055/s-0031-1289698; Art ID: H106311SS
© Georg Thieme Verlag Stuttgart · New York

712
Z.-K. Xiao, L.-X. Shao
PAPER
the yield of 7 can be increased to 80% in toluene within
three hours (Table 3, entry 4); this was drastically de-
creased to 61% when the ratio of 2a to 5 was further in-
creased to 2:1 (Table 3, entry 5). It is worthy to note here
that we found at this stage that the reaction performed in
toluene is reversible. For instance, when the reaction be-
tween 2a and 5 (1.5:1) was performed with prolonged
time (6 h), product 6 was observed in 26% yield, along
with product 7 in 43% yield (Table 3, entry 4 vs entry 6).
Table 1 Optimization of the Complex 1 Catalyzed Reaction of 2a
with 3a
Cl
NHC-Pd(II)-Im 1
(1.0 mol%)
O
O
+
base (2.0 equiv)
solvent, 80 °C
OMe
OMe
2a
3a
4a
Entrya
Base
Solvent
Yieldb (%)
We believe in this case that two different enolates derived
from 6 will be formed in N,N-dimethylformamide and tol-
uene (Scheme 1). For example, the thermally stable eno-
late 6¢ may be mainly obtained in a polar solvent such as
N,N-dimethylformamide, while the dynamically stable
1
2
KOt-Bu
NaOt-Bu
KOH
THF
68
13
33
18
–
THF
3
THF
4
NaOH
Cs2CO3
LiOt-Bu
KOt-Bu
KOt-Bu
KOt-Bu
KOt-Bu
KOt-Bu
THF
Table 2 Complex 1 Catalyzed a-Arylation of Ketones with Aryl
Chlorides
5
THF
6
THF
12
59
40
–
O
Cl
O
NHC-Pd(II)-Im 1
R3
R1
(1.0 mol%)
R3
7
DME
toluene
MeCN
DMF
DMF
+
KOt-Bu, solvent
80 °C, 6 h
8
R2
R1
R2
9
2
3
4
10
11c
78
90
Entrya
2
3
Solvent
Yieldb
(%)
(R1)
(R2, R3)
a Reaction conditions (unless otherwise specified): 2a (1.0 equiv), 3a
(1.0 mmol), 1 (1.0 mol%), base (2.0 equiv), solvent (1.0 mL), 80 °C,
24 h.
1
2
3
4
5
6
7
2b (H)
3a (H, Me)
DMF
DMF
DMF
DMF
DMF
DMF
4b, 82
4c, 83
4d, 93
4e, 93
4f, 55
4g, 70
2c (3-OMe)
2d (4-Me)
2e (3-Me)
2f (2-Me)
2c
3a
b Isolated yield.
3a
c 1.2 Equivalents of 2a were used and the time was 3 h.
3a
on the substrates 2 and 3 have some effect on the reaction.
For instance, reaction of the sterically hindered substrate
2-methylphenyl chloride (2f) with 1-phenylpropan-1-one
(3a) only gave product 4f in 55% yield (Table 2, entry 5).
Slightly lower yields were observed when electron-poor
1-(4-fluorophenyl)propan-1-one (3d) was used as the sub-
strate (Table 2, entries 11–13). Further studies showed
that electron-poor aryl chlorides are not suitable in this a-
arylation reaction. For example, only very low yields can
be observed when 4-formylphenyl chloride, 4-cyanophe-
nyl chloride, 4-nitrophenyl chloride and 4-fluorophenyl
chloride were used as the substrates.
3a
3b (4-Me, Me)
2a (4-OMe)
3b
DMF
toluene
4h, 81
4h, 91
8
9
2a
2d
2e
2a
2d
2e
2a
3c (4-OMe, Me)
DMF
toluene
4i, 55
4i, 89
3c
DMF
toluene
4j, 75
4j, 80
10
11
12
13
14
3c
DMF
toluene
4k, 74
4k, 63
Furthermore, the reaction between 4-methoxyphenyl
chloride (2a) and pentan-3-one (5) was also investigated
and a drastic solvent effect was observed in this case. For
example, in the first round, the reaction was carried out
under the optimal conditions in N,N-dimethylformamide,
and the monoarylated product 6 was obtained as the sole
product in 42% yield within six hours (Table 3, entry 1);
this result was not disturbed when the ratio of 2a to 5 was
increased to 2:1 (Table 3, entry 2). When we attempted to
increase the yield of product 6 by changing the solvent to
toluene, to our surprise, the diarylated product 7 was
achieved as the sole product in 67% yield within three
hours instead of the monoarylated product 6 (Table 3, en-
try 3). By further increasing the ratio of 2a to 5 to 1.5:1,
3d (4-F, Me)
3d
DMF
toluene
4l, 23
4l, 73
DMF
toluene
4m, 52
4m, 68
3d
DMF
toluene
4n, 50
4n, 60
3e (H, H)
DMF
toluene
THF
4o, 50
4o, 36
4o, 73
a Reaction conditions: 2 (1.2 equiv), 3 (1.0 mmol), 1 (1.0 mol%),
KOt-Bu (2.0 equiv), solvent (1.0 mL), 80 °C, 6 h.
b Isolated yield.
Synthesis 2012, 44, 711–716
© Thieme Stuttgart · New York

PAPER
a-Arylation of Ketones with Aryl Chlorides
713
yield (Scheme 2), which clearly reveals the occurrence of
the retroarylation reaction and explains well the results
shown in Table 3, entry 6.
Table 3 Complex 1 Catalyzed Reaction of 2a with Pentan-3-one (5)
in Different Solvents
OMe
Thus, although the actual mechanism for the retroaryla-
tion reaction still remains unclear at this stage, a plausible
mechanism based on the above results is shown in
Scheme 3. First, the catalytically active palladium(0),
generated from NHC–Pd(II)–Im complex 1,6c might un-
dergo oxidative addition to 7 to give intermediate 8 (for
convenience, the corresponding ligands on the metal cen-
ter have been omitted in all of the intermediates). Second-
ly, ligand substitution by the enolate 9 derived from
pentan-3-one (5) might provide intermediate 11, along
with the release of intermediate 10. Finally, reductive
elimination of intermediate 11 or hydrolysis of intermedi-
ate 10 would afford product 6.
O
MeO
Cl
NHC-Pd(II)-Im 1
6
(1.0 mol%)
2a
+
O
and/or
KOt-Bu, solvent, 80 °C
OMe
OMe
5
O
7
Entrya
2a/5
Solvent
Time (h) Yieldb (%)
6
7
1
2
3
4
5
6
1.2:1
2:1
DMF
6
6
3
3
3
6
42
41
–
–
O
KOt-Bu
DMF
–
t-BuOH
O–
5
1.2:1
1.5:1
2:1
toluene
toluene
toluene
toluene
67
80
61
43
O
K+
O–
R1
–
O
9
Pd R1
K+
R1
R1
–
7
8
1.5:1
26
R1
2 KR2 +
solvent
a Reaction conditions: 5 (1.0 mmol), 1 (1.0 mol%), KOt-Bu (2.0
equiv), solvent (1.0 mL), 80 °C.
10
R1 = 4-MeOC6H4
O
t-BuOH
b Isolated yield.
1
Pd(0)
Pd
O
R2-R2
2 KCl
O–
+
R1
11
enolate 6¢¢ will be mainly formed in a nonpolar solvent
such as toluene; enolate 6¢¢ is a key intermediate for the di-
arylated product 7.
R2
=
R1
6
6
To further clarify the retroarylation pathway, we also
treated the diarylated product 7 (0.5 mmol) under the
same conditions in the presence of pentan-3-one (5, 2.0
equiv). It was found that the monoarylated product 6 can
be obtained in 28% yield, along with recovered 7 in 49%
Scheme 3 Proposed mechanism for the retroarylation reaction
In summary, the easily available, well-defined NHC–
Pd(II)–Im complex 1, derived from the starting materials
IPr·HCl, PdCl2 and 1-methylimidazole, showed good cat-
alytic activity in the a-arylation of ketones with aryl chlo-
rides as the substrates under mild conditions. Compared to
the previously reported NHC–Pd(II) complexes used in a-
arylation reactions with aryl chlorides as the substrates,
the NHC–Pd(II)–Im complex 1 reported in this paper is
easier to synthesize in a one-step process, and similar
yields can be achieved.
OMe
OMe
KOt-Bu
KO
O
DMF
KOt-Bu
toluene
6
6'
OMe
KO
1H and 13C NMR spectra were recorded on a Bruker AV-II 300
MHz or Bruker AV-III 500 MHz spectrometer for solutions in
CDCl3 with tetramethylsilane (TMS) as an internal standard; J val-
ues are given in Hz. Commercially obtained reagents were used
without further purification. Flash column chromatography was
carried out using Huanghai silica gel (300–400 mesh) at increased
pressure.
6''
Scheme 1 Different enolates derived from 6 in N,N-dimethylform-
amide and toluene
O
R
R
NHC-Pd(II)-Im 1
O
7
+
O
(1.0 mol%)
1,2-Diarylalkan-1-ones 4; General Procedure for the Complex 1
Catalyzed a-Arylation Reaction
Under N2 atmosphere, NHC–Pd(II)–Im complex 1 (6.5 mg, 1.0
mol%) and KOt-Bu (224.4 mg, 2.0 mmol), the indicated solvent
(1.0 mL), a ketone 3 (1.0 mmol) and an aryl chloride 2 (1.2 mmol)
were successively added to a Schlenk reaction tube. Then, the mix-
recovered 7
+
KOt-Bu, toluene
80 °C, 10 h
R = 4-MeOC6H4
49%
R
6
28%
5
Scheme 2 Control experiment
© Thieme Stuttgart · New York
Synthesis 2012, 44, 711–716

714
Z.-K. Xiao, L.-X. Shao
PAPER
2-(3-Methoxyphenyl)-1-(4-methylphenyl)propan-1-one (4g)
Colorless liquid; yield: 177.4 mg (70%).
IR (neat): 1678, 1607, 1263, 1181, 956, 785, 736, 699 cm–1.
1H NMR (500 MHz, CDCl3): d = 1.51 (d, J = 6.5 Hz, 3 H, Me), 2.35
(s, 3 H, Me), 3.76 (s, 3 H, OMe), 4.63 (q, J = 6.5 Hz, 1 H), 6.73 (dd,
J = 2.0, 8.0 Hz, 1 H, Ar), 6.81 (t, J = 1.5 Hz, 1 H, Ar), 6.87 (d,
J = 8.0 Hz, 1 H, Ar), 7.17–7.22 (m, 3 H, Ar), 7.86 (d, J = 8.0 Hz, 2
H, Ar).
13C NMR (125 MHz, CDCl3): d = 19.4, 21.5, 47.7, 55.2, 112.1,
113.4, 120.2, 128.9, 129.1, 129.9, 134.0, 143.3, 143.5, 160.0, 199.7.
ture was stirred at 80 °C for 6 h. The reaction mixture was cooled to
r.t., then was diluted with EtOAc (15 mL), washed with brine (15
mL) and dried over anhyd Na2SO4 (in the case of DMF as the sol-
vent). The solvent was evaporated under reduced pressure and the
residue was purified by flash column chromatography on silica gel
to give the pure product.
2-(4-Methoxyphenyl)-1-phenylpropan-1-one (4a)5d
Colorless liquid; yield: 216.6 mg (90%).
1H NMR (500 MHz, CDCl3): d = 1.50 (d, J = 7.0 Hz, 3 H, Me), 3.74
(s, 3 H, OMe), 4.64 (q, J = 7.0 Hz, 1 H), 6.82 (d, J = 8.5 Hz, 2 H,
Ar), 7.20 (d, J = 8.5 Hz, 2 H, Ar), 7.35–7.48 (m, 3 H, Ar), 7.94 (dd,
J = 1.0, 8.5 Hz, 2 H, Ar).
HRMS (ESI): m/z calcd for C17H18O2Na+: 277.1199; found:
277.1189.
13C NMR (125 MHz, CDCl3): d = 19.5, 47.0, 55.2, 114.4, 128.4,
2-(4-Methoxyphenyl)-1-(4-methylphenyl)propan-1-one (4h)
Colorless liquid; yield: 231.4 mg (91%).
128.7, 128.8, 132.7, 133.5, 136.6, 158.5, 200.6.
1,2-Diphenylpropan-1-one (4b)6c
Yellow liquid; yield: 172.4 mg (82%).
IR (neat): 1678, 1607, 1510, 1456, 1246, 1177, 1037, 831, 770, 736,
703 cm–1.
1H NMR (500 MHz, CDCl3): d = 1.54 (d, J = 7.0 Hz, 3 H, Me), 4.67
(q, J = 7.0 Hz, 1 H), 7.18–7.22 (m, 1 H, Ar), 7.28–7.31 (m, 4 H, Ar),
7.36–7.39 (m, 2 H, Ar), 7.46–7.49 (m, 1 H, Ar), 7.95 (d, J = 8.0 Hz,
2 H, Ar).
1H NMR (500 MHz, CDCl3): d = 1.49 (d, J = 6.5 Hz, 3 H, Me), 2.34
(s, 3 H, Me), 3.74 (s, 3 H, OMe), 4.62 (q, J = 6.5 Hz, 1 H), 6.81 (d,
J = 8.5 Hz, 2 H, Ar), 7.17 (d, J = 8.5 Hz, 2 H, Ar), 7.19 (d, J = 8.5
Hz, 2 H, Ar), 7.85 (d, J = 8.5 Hz, 2 H, Ar).
13C NMR (125 MHz, CDCl3): d = 19.4, 47.8, 126.8, 127.7, 128.4,
128.7, 128.9, 132.7, 136.5, 141.4, 200.2.
13C NMR (125 MHz, CDCl3): d = 19.5, 21.5, 46.8, 55.1, 114.3,
128.7, 128.8, 129.1, 133.7, 134.0, 143.4, 158.4, 200.1.
HRMS (ESI): m/z calcd for C17H18O2Na+: 277.1199; found:
277.1189.
2-(3-Methoxyphenyl)-1-phenylpropan-1-one (4c)5a
Colorless liquid; yield: 199.4 mg (83%).
1H NMR (300 MHz, CDCl3): d = 1.52 (d, J = 6.9 Hz, 3 H, Me), 3.76
(s, 3 H, OMe), 4.65 (q, J = 6.9 Hz, 1 H), 6.74 (dd, J = 2.7, 8.4 Hz, 1
H, Ar), 6.81–6.89 (m, 2 H, Ar), 7.18–7.23 (m, 1 H, Ar), 7.37–7.47
(m, 3 H, Ar), 7.95 (dd, J = 1.5, 8.7 Hz, 2 H, Ar).
13C NMR (125 MHz, CDCl3): d = 19.4, 47.9, 55.2, 112.2, 113.5,
120.2, 128.4, 128.7, 129.9, 132.7, 136.5, 143.0, 160.0, 200.1.
1,2-Bis(4-methoxyphenyl)propan-1-one (4i)9
Colorless liquid; yield: 240.2 mg (89%).
1H NMR (500 MHz, CDCl3): d = 1.49 (d, J = 7.0 Hz, 3 H, Me), 3.74
(s, 3 H, OMe), 3.81 (s, 3 H, OMe), 4.59 (q, J = 7.0 Hz, 1 H), 6.82
(d, J = 8.5 Hz, 2 H, Ar), 6.85 (d, J = 9.0 Hz, 2 H, Ar), 7.19 (d,
J = 8.5 Hz, 2 H, Ar), 7.94 (d, J = 9.0 Hz, 2 H, Ar).
13C NMR (125 MHz, CDCl3): d = 19.5, 46.6, 55.1, 55.3, 113.6,
114.3, 128.7, 129.5, 131.0, 133.9, 158.4, 163.1, 199.1.
2-(4-Methylphenyl)-1-phenylpropan-1-one (4d)5d
Colorless liquid; yield: 209.0 mg (93%).
1H NMR (500 MHz, CDCl3): d = 1.50 (d, J = 7.0 Hz, 3 H, Me), 2.28
(s, 3 H, Me), 4.64 (q, J = 7.0 Hz, 1 H), 7.08 (d, J = 8.0 Hz, 2 H, Ar),
7.16 (d, J = 8.0 Hz, 2 H, Ar), 7.37 (t, J = 7.5 Hz, 2 H, Ar), 7.47 (t,
J = 7.5 Hz, 1 H, Ar), 7.94 (d, J = 7.5 Hz, 2 H, Ar).
13C NMR (125 MHz, CDCl3): d = 19.5, 21.0, 47.5, 127.6, 128.4,
128.7, 129.7, 132.7, 136.5, 136.6, 138.5, 200.5.
1-(4-Methoxyphenyl)-2-(4-methylphenyl)propan-1-one (4j)10
Colorless liquid; yield: 202.7 mg (80%).
1H NMR (500 MHz, CDCl3): d = 1.49 (d, J = 7.0 Hz, 3 H, Me), 2.28
(s, 3 H, Me), 3.81 (s, 3 H, OMe), 4.60 (q, J = 7.0 Hz, 1 H), 6.85 (d,
J = 9.0 Hz, 2 H, Ar), 7.09 (d, J = 8.0 Hz, 2 H, Ar), 7.17 (d, J = 8.0
Hz, 2 H, Ar), 7.94 (d, J = 9.0 Hz, 2 H, Ar).
13C NMR (125 MHz, CDCl3): d = 19.5, 20.9, 47.1, 55.3, 113.6,
127.5, 129.5, 129.6, 131.0, 136.3, 138.9, 163.1, 199.0.
2-(3-Methylphenyl)-1-phenylpropan-1-one (4e)8
Colorless liquid; yield: 208.3 mg (93%).
1H NMR (500 MHz, CDCl3): d = 1.52 (d, J = 6.5 Hz, 3 H, Me), 2.30
(s, 3 H, Me), 4.65 (q, J = 6.5 Hz, 1 H), 7.01 (d, J = 7.5 Hz, 1 H, Ar),
7.09 (s, 2 H, Ar), 7.16–7.19 (m, 1 H, Ar), 7.36–7.39 (m, 2 H, Ar),
7.45–7.48 (m, 1 H, Ar), 7.96 (d, J = 8.0 Hz, 2 H, Ar).
13C NMR (125 MHz, CDCl3): d = 19.5, 21.4, 47.8, 124.9, 127.7,
128.3, 128.4, 128.76, 128.80, 132.7, 136.5, 138.6, 141.4, 200.4.
1-(4-Methoxyphenyl)-2-(3-methylphenyl)propan-1-one (4k)10
Colorless liquid; yield: 160.0 mg (63%).
1H NMR (300 MHz, CDCl3): d = 1.50 (d, J = 6.9 Hz, 3 H, Me), 2.30
(s, 3 H, Me), 3.81 (s, 3 H, OMe), 4.60 (q, J = 6.9 Hz, 1 H), 6.85 (d,
J = 9.0 Hz, 2 H, Ar), 6.99–7.20 (m, 4 H, Ar), 7.93 (d, J = 9.0 Hz, 2
H, Ar).
13C NMR (125 MHz, CDCl3): d = 19.5, 21.4, 47.5, 55.3, 113.6,
124.8, 127.5, 128.2, 128.8, 129.5, 131.0, 138.5, 141.8, 163.2, 198.9.
2-(2-Methylphenyl)-1-phenylpropan-1-one (4f)5d
Colorless liquid; yield: 124.1 mg (55%).
1H NMR (500 MHz, CDCl3): d = 1.47 (d, J = 6.5 Hz, 3 H, Me), 2.50
(s, 3 H, Me), 4.76 (q, J = 6.5 Hz, 1 H), 7.02 (d, J = 7.5 Hz, 1 H, Ar),
7.06–7.09 (m, 2 H, Ar), 7.20 (d, J = 7.0 Hz, 1 H, Ar), 7.35 (t, J = 7.5
Hz, 2 H, Ar), 7.45 (t, J = 7.5 Hz, 1 H, Ar), 7.82 (d, J = 8.0 Hz, 2 H,
Ar).
13C NMR (125 MHz, CDCl3): d = 18.0, 19.6, 44.6, 126.8, 126.9,
127.0, 128.5, 130.9, 132.6, 134.5, 136.6, 140.1, 201.0.
1-(4-Fluorophenyl)-2-(4-methoxyphenyl)propan-1-one (4l)
Yellow liquid; yield: 189.1 mg (73%).
IR (neat): 1682, 1597, 1508, 1224, 1178, 1156, 1033, 953, 909, 831,
780, 730 cm–1.
1H NMR (500 MHz, CDCl3): d = 1.49 (d, J = 6.5 Hz, 3 H, Me), 3.74
(s, 3 H, OMe), 4.58 (q, J = 6.5 Hz, 1 H), 6.83 (d, J = 8.5 Hz, 2 H,
Ar), 7.01–7.05 (m, 2 H, Ar), 7.17 (d, J = 8.0 Hz, 2 H, Ar), 7.95–7.98
(m, 2 H, Ar).
Synthesis 2012, 44, 711–716
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a-Arylation of Ketones with Aryl Chlorides
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13C NMR (125 MHz, CDCl3): d = 19.4, 47.0, 55.1, 114.4, 115.5 (d,
JC-F = 21.6 Hz), 128.7, 131.3 (d, JC-F = 9.1 Hz), 132.8 (d, JC-F = 3.0
Hz), 133.3, 158.5, 165.3 (d, JC-F = 252.9 Hz), 198.9.
HRMS (ESI): m/z calcd for C16H15FO2Na+: 281.0948; found:
281.0942.
Acknowledgment
Financial support from the Opening Foundation of Zhejiang Provin-
cial Top Key Discipline (No. 100061200123) is gratefully acknow-
ledged. Z.-K.X. thanks the Science and Technology Department of
Zhejiang Province (Xinmiao Program) for financial support (No.
2011R424042).
1-(4-Fluorophenyl)-2-(4-methylphenyl)propan-1-one (4m)10
Colorless liquid; yield: 165.4 mg (68%).
1H NMR (300 MHz, CDCl3): d = 1.50 (d, J = 6.9 Hz, 3 H, Me), 2.28
(s, 3 H, Me), 4.59 (q, J = 6.9 Hz, 1 H), 7.00–7.16 (m, 6 H, Ar), 7.94–
7.99 (m, 2 H, Ar).
References
(1) (a) Tsuji, J. Palladium Reagents and Catalysis: Innovations
in Organic Synthesis; Wiley: New York, 1995. (b) Metal-
Catalyzed Cross-Coupling Reactions; Diederich, F.; Stang,
P. J., Eds.; Wiley-VCH: Weinheim, 1998. (c) Handbook of
Organopalladium Chemistry for Organic Synthesis;
Negishi, E.-i.; de Meijere, A., Eds.; John Wiley & Sons:
New York, 2002. (d) Metal-Catalyzed Cross-Coupling
Reactions, Vols. 1 and 2; de Meijere, A.; Diederich, F., Eds.;
Wiley-VCH: Weinheim, 2004.
(2) For some initial examples, see: (a) Fauvarque, J. F.; Jutand,
A. J. Organomet. Chem. 1979, 177, 273. (b) Galarini, R.;
Musco, A.; Pontellini, R.; Santi, R. J. Mol. Catal. 1992, 72,
L11. (c) Kuwajima, I.; Nakamura, E.-i. Acc. Chem. Res.
1985, 18, 181. (d) Kosugi, M.; Hagiwara, I.; Sumiya, T.;
Migita, T. Bull. Chem. Soc. Jpn. 1985, 58, 3383.
13C NMR (125 MHz, CDCl3): d = 19.5, 21.0, 47.6, 115.5 (d, JC-F
21.6 Hz), 127.5, 129.8, 131.4 (d, JC-F = 9.1 Hz), 132.9 (d, JC-F = 3.0
Hz), 136.6, 138.3, 165.4 (d, JC-F = 252.9 Hz), 198.8.
=
1-(4-Fluorophenyl)-2-(3-methylphenyl)propan-1-one (4n)10
Yellow liquid; yield: 144.7 mg (60%).
1H NMR (300 MHz, CDCl3): d = 1.51 (d, J = 6.6 Hz, 3 H, Me), 2.30
(s, 3 H, Me), 4.58 (q, J = 6.6 Hz, 1 H), 7.01–7.06 (m, 5 H, Ar), 7.16–
7.21 (m, 1 H, Ar), 7.95–8.00 (m, 2 H, Ar).
13C NMR (125 MHz, CDCl3): d = 19.5, 21.4, 47.9, 115.5 (d, JC-F
21.8 Hz), 124.8, 127.8, 128.2, 128.9, 131.4 (d, JC-F = 9.1 Hz), 132.9
(d, JC-F = 2.9 Hz), 138.7, 141.3, 165.4 (d, JC-F = 253.0 Hz), 198.8.
=
(3) For some selected examples using ketones as the substrate,
see: (a) Palucki, M.; Buchwald, S. L. J. Am. Chem. Soc.
1997, 119, 11108. (b) Hamann, B. C.; Hartwig, J. F. J. Am.
Chem. Soc. 1997, 119, 12382. (c) Satoh, T.; Kawamura, Y.;
Miura, M.; Nomura, M. Angew. Chem., Int. Ed. Engl. 1997,
36, 1740. (d) Culkin, D. A.; Hartwig, J. F. Acc. Chem. Res.
2003, 36, 234. (e) Huang, J.-K.; Bunel, E.; Faul, M. M. Org.
Lett. 2007, 9, 4343. (f) Hama, T.; Hartwig, J. F. Org. Lett.
2008, 10, 1545. (g) Hama, T.; Hartwig, J. F. Org. Lett. 2008,
10, 1549. (h) Biscoe, M. R.; Buchwald, S. L. Org. Lett.
2009, 11, 1773. (i) Liao, X.-B.; Weng, Z.-Q.; Hartwig, J. F.
J. Am. Chem. Soc. 2008, 130, 195. (j) Miura, M.; Satoh, T.
In Palladium in Organic Synthesis, Vol. 14; Tsuji, J., Ed.;
Springer: Berlin, 2005.
(4) For reviews of NHC–palladium complexes in coupling
reactions, see: (a) Hillier, A. C.; Grasa, G. A.; Viciu, M. S.;
Lee, H. M.; Yang, C.-L.; Nolan, S. P. J. Organomet. Chem.
2002, 653, 69. (b) Kantchev, E. A. B.; O’Brien, C. J.; Organ,
M. G. Angew. Chem. Int. Ed. 2007, 46, 2768. (c) Marion,
N.; Nolan, S. P. Acc. Chem. Res. 2008, 41, 1440.
2-(4-Methoxyphenyl)-1-phenylethanone (4o)6c
Pale yellow solid; yield: 165.7 mg (73%); mp 52–53 °C.
1H NMR (300 MHz, CDCl3): d = 3.79 (s, 3 H, OMe), 4.23 (s, 2 H),
6.87 (d, J = 8.7 Hz, 2 H, Ar), 7.18 (d, J = 8.7 Hz, 2 H, Ar), 7.46 (t,
J = 7.2 Hz, 2 H, Ar), 7.55 (t, J = 7.2 Hz, 1 H, Ar), 7.99–8.02 (m, 2
H, Ar).
13C NMR (125 MHz, CDCl3): d = 44.6, 55.2, 114.2, 126.5, 128.59,
128.61, 130.4, 133.1, 136.6, 158.6, 198.0.
2-(4-Methoxyphenyl)pentan-3-one (6)11
Yellow liquid; yield: 79.2 mg (41%).
1H NMR (500 MHz, CDCl3): d = 0.96 (t, J = 7.0 Hz, 3 H, Me), 1.36
(d, J = 7.0 Hz, 3 H, Me), 2.29–2.45 (m, 2 H), 3.71 (q, J = 7.0 Hz, 1
H), 3.79 (s, 3 H, OMe), 6.86 (d, J = 8.5 Hz, 2 H, Ar), 7.13 (d, J = 8.5
Hz, 2 H, Ar).
13C NMR (125 MHz, CDCl3): d = 8.0, 17.5, 34.0, 51.7, 55.2, 114.2,
128.8, 132.9, 158.6, 211.8.
(d) Fortman, G. C.; Nolan, S. P. Chem. Soc. Rev. 2011, 40,
5151.
(5) For Nolan’s contributions, see: (a) Viciu, M. S.;
Germaneau, R. F.; Nolan, S. P. Org. Lett. 2002, 4, 4053.
(b) Viciu, M. S.; Kelly, R. A. III; Stevens, E. D.; Naud, F.;
Studer, M.; Nolan, S. P. Org. Lett. 2003, 5, 1479.
2,4-Bis(4-methoxyphenyl)pentan-3-one (7)
White solid; yield: 178.8 mg (80%); mp 81–82 °C.
IR (neat): 1713, 1508, 1463, 1258, 1240, 1176, 1057, 1030, 835,
820, 790 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.22 (d, J = 6.9 Hz, 6 H, 2 Me),
3.72 (q, J = 6.9 Hz, 2 H), 3.81 (s, 6 H, 2 OMe), 6.87 (d, J = 8.7 Hz,
4 H, Ar), 7.09 (d, J = 8.7 Hz, 4 H, Ar).
13C NMR (125 MHz, CDCl3): d = 18.1, 49.8, 55.3, 114.4, 129.0,
133.1, 158.7, 210.8.
(c) Navarro, O.; Marion, N.; Scott, N. M.; González, J.;
Amoroso, D.; Bell, A.; Nolan, S. P. Tetrahedron 2005, 61,
9716. (d) Navarro, O.; Marion, N.; Oonishi, Y.; Kelly, R. A.
III; Nolan, S. P. J. Org. Chem. 2006, 71, 685. (e) Marion,
N.; Ecarnot, E. C.; Navarro, O.; Amoroso, D.; Bell, A.;
Nolan, S. P. J. Org. Chem. 2006, 71, 3816. (f) Marion, N.;
de Frémont, P.; Puijk, I. M.; Ecarnot, E. C.; Amoroso, D.;
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(6) For the contributions of some others, see: (a)Lee, S.; Beare,
N. A.; Hartwig, J. F. J. Am. Chem. Soc. 2001, 123, 8410.
(b) Kündig, E. P.; Seidel, T. M.; Jia, Y.-X.; Bernardinelli, G.
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Wang, L.-L.; Cai, Z.-Y.; Zhang, L.-Q.; Guo, J.; Pang, G.-S.;
Shi, Y.-H. Eur. J. Org. Chem. 2011, 1570. (d) Zhang, J.-L.;
Yang, X.-Q.; Cui, X.-L.; Wu, Y.-J. Tetrahedron 2011, 67,
8800.
HRMS (ESI): m/z calcd for C19H22O3Na+: 321.1461; found:
321.1453.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.
© Thieme Stuttgart · New York
Synthesis 2012, 44, 711–716

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2011, 696, 3741. (d) Gu, Z.-S.; Shao, L.-X.; Lu, J.-M.
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Synthesis 2012, 44, 711–716
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