Copper-catalyzed arylation of arylboronic acids with aldehydes

Article abstract of DOI:10.1055/s-0030-1260789

A novel copper-catalyzed arylation of arylboronic acids with aldehydes under oxygen atmosphere was achieved in the presence of Cu(OTf)₂ and Xantphos, affording diaryl ketone derivatives in moderate to good yields. The efficiency of this reaction was demonstrated by the compatibility with fluoro, bromo, chloro, nitro, -methylsulfonyl, and trifluoromethyl groups. Georg Thieme Verlag Stuttgart ? New York.

Full text of DOI:10.1055/s-0030-1260789

1626
LETTER
Copper-Catalyzed Arylation of Arylboronic Acids with Aldehydes
C
opper-Catalyzed
a
A
rylation
o
n
f
A
rylboroni
m
c
Acids
w
ith Aldeh
e
ydes i Zheng,a Jinchang Ding,a,b Jiuxi Chen,*a Miaochang Liu,a Wenxia Gao,a Huayue Wu*a
a
College of Chemistry and Materials Engineering, Wenzhou University, Wenzhou 325035, P. R. of China
Fax +86(577)88368280; E-mail: jiuxichen@wzu.edu.cn; E-mail: huayuewu@wzu.edu.cn
Wenzhou Vocational & Technical College, Wenzhou 325035, P. R. of China
b
Received 1 February 2011
of aldehydes to produce diaryl ketones in good yields.16
Recently, Xu and co-workers have reported palladium-
catalyzed direct C–H bond arylation of 2-hydroxybenzal-
dehydes with arylboronic acids.17 Although another new
Abstract: A novel copper-catalyzed arylation of arylboronic acids
with aldehydes under oxygen atmosphere was achieved in the pres-
ence of Cu(OTf)2 and Xantphos, affording diaryl ketone derivatives
in moderate to good yields. The efficiency of this reaction was dem-
onstrated by the compatibility with fluoro, bromo, chloro, nitro, method has also been developed, it suffered from the lim-
methylsulfonyl, and trifluoromethyl groups.
ited range of 2-hydroxybenzaldehydes.
Key words: arylation, diaryl ketones, copper, catalysis
Recently, the use of copper salts as catalysts has gained
much prominence in organic synthesis due to their eco-
nomic attractiveness, good functional group tolerance,
and scalability in large-scale synthetic procedures.18 Very
recently, we have reported the copper-catalyzed synthesis
of carbinol derivatives by addition of arylboronic acids to
aromatic aldehydes in good to excellent yields.19
Diaryl ketone derivatives constitute an important building
block for the synthesis of natural products and pharmaco-
logically active compounds.1 Common synthetic routes
for the preparation of these compounds involve Friedel–
Crafts acylation reactions2 and acylation reactions using
organometallic reagents.3 However, these methods suffer
from a lack of atom economy because a stoichiometric
amount of aluminum trichloride is used. Anhydrous con-
ditions are often required for both partners. Alternative
approaches to construct diaryl ketones include metal-cat-
alyzed coupling reactions of carboxylic acid derivatives
such as acyl halides,4 carboxylic anhydrides,5 esters,6 or
thiol esters7 with organometallic compounds. These re-
ports, nevertheless, either had a limited substrate scope or
required additives.
To our knowledge, a general and efficient copper-cata-
lyzed method for the arylation of arylboronic acids with
aldehydes to give the corresponding diaryl ketone deriva-
tives has not been developed. Continuation of our interest
in the development of organoboron reactions led us to ex-
plore the potential reactions between organoboron re-
agents and aldehydes or aldimines.16,19,20 Herein, we
report that copper-catalyzed arylation of arylboronic acids
with aldehydes, using Xantphos as the ligand under oxy-
gen atmosphere, provides diaryl ketone derivatives with
yields ranging from moderate to good.
Some other general methods involve reactions between an
aryl halide and an aldehyde or its derivative catalyzed by
palladium,8 rhodium,9 or nickel.10 Chang and co-workers
have reported cooperative catalysis by Ru and Pd for the
direct coupling of a chelating aldehyde with iodoarenes or
organostannanes.11 The high availability of aldehydes
renders this route particularly attractive.
As suggested by our previous work,19 initial studies fo-
cused on screening of oxidative additives, bases, and sol-
vents using Cu(OAc)2·H2O as the copper source and dppf
as the ligand with the reaction of 4-nitrobenzaldehyde
(1a) and phenylboronic acid (2a) as a model reaction.
Screening results are listed in Table 1. No target product
was detected in the presence of various oxidative addi-
tives such as PhI(OAc)2, Ag2O, DDQ, and Oxone
(Table 1, entries 1–4). However, it was satisfying to find
that the reaction could proceed and afforded 3aa in 12%
yield when the combination of CsF and toluene was em-
ployed under air (Table 1, entry 13).
Organoboron reagents are highly regarded due to their ad-
vantages of stability to air and moisture, and good func-
tional group tolerance.12 In recent years, the method for
the synthesis of diaryl ketones by palladium-13 and
nickel14-catalyzed addition of arylboronic acids to nitriles
has been developed. However, less attention has been paid
to the synthesis of diaryl ketones by the reaction of alde-
hydes with organoboron reagents. In 2004, Genet and co-
workers reported the direct access to ketones from alde-
hydes via rhodium-catalyzed cross-coupling reaction with
potassium trifluoro(organo)borates.15 In our previous re-
port, we have developed a palladium-catalyzed arylation
Considering ligands always play important roles in metal-
catalyzed chemistry,21 we focused on ligand screening
(Scheme 1). Through screening, we found that bidentate
phosphine ligands with electron-rich, large bite angles, or
small bite angles had poor catalytic activity (Scheme 1,
L1–L5). The small hindrance of the monodentate phos-
phine ligands resulted in poor yields (Scheme 1, L6, L8,
and L9). Electron-rich phosphine ligands such as Xant-
phos (L13) were effective for this transformation, afford-
ing 42% yield. In addition, we examined the
aminophosphine ligands (Scheme 1, L15–L17) and nitro-
SYNLETT 2011, No. 11, pp 1626–1630
x
x
.x
x
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1
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Advanced online publication: 15.06.2011
DOI: 10.1055/s-0030-1260789; Art ID: W03811ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Copper-Catalyzed Arylation of Arylboronic Acids with Aldehydes
1627
Table 1 Selected Results of Screening for Optimal Conditionsa
O
Cu(OAc)2⋅H2O,
L
O
Cu(OAc)2⋅H2O, dppf
O2N
CHO
+
PhB(OH)2
+
O2N
CHO
PhB(OH)2
O2N
CsF, toluene
base, additive, solvent
O2N
Ph
2a
1a
dppf
3aa
1a
2a
3aa
dppe
dppp
dppb
Entry Base
Additive
PhI(OAc)2
Solvent
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
Yield (%)b
L1 12%
L2 23%
L3 20%
L4 27%
(S)-binap
Ph3P
P(4-MeO-Ph)3
P(2-Tol)3
1
2
NaOAc
NaOAc
<5
<5
<5
<5
<5
<5
<5
<5
<5
5
L5 38.5%
L6 10%
L7 <5%
L8 15%
Ag2O
DDQ
Oxone
P(2-Furan)3
P(1-Nap)3
P(3,5-di-Tol)3
P(C6F5)3
L9 21%
L10 <5%
L11 9%
L12 11%
3
NaOAc
NaOAc
NaOAc
NaOH
CsOH
Na2CO3
K2CO3
Cs2CO3
DABCO
KOt-Bu
CsF
Xantphos
DPEphos
i-Pr2NP(2-Tol)2
i-Pr2NPPh2
4
L13 42%
L14 11%
L15 <5%
L16 38%
N
N
5
L
-Proline
bpy
L19 <5%
N
PPh2
L18 <5%
6
L20 <5%
L17 33%
7
8
N
N
N
N
N
N
L22 <5%
L21 <5%
9
L23 <5%
Scheme 1 Ligand screening. Reagents and conditions: 1a (0.3
mmol), 2a (0.6 mmol), base (0.9 mmol), Cu(OAc)2·H2O (10 mol%),
ligand (10 mol%), CsF (0.9 mmol), air, toluene (2 mL), 120 °C, 24 h.
Isolated yields are given.
10
11
12
13
14
15
16
17
18
<5
<5
12
yield was improved to 85% when the reaction was carried
out under oxygen (Table 2, entry 18).
CsF
chlorobenzene 10
With optimal conditions in hand, the reaction of different
aldehydes with various arylboronic acids was examined to
explore the scope of the reaction (Table 3). In our system,
the electronic effect of substituents on the arylboronic ac-
ids had little influence on the reaction (Table 3, entries 1–
6). Electron-neutral 2a and electron-rich 2b,c arylboronic
acids reacted smoothly with 4-nitrobenzaldehyde (1a) to
afford 3aa, 3ab, and 3ac in 85%, 86%, and 72% yields, re-
spectively (Table 3, entries 1–3). Electron-withdrawing
arylboronic acids, which are less nucleophilic, and hence
transmetalate more slowly than their electron-neutral ana-
logues, are prone to homocoupling and protodeboronation
side reactions.21c However, in our catalytic system, 4-bro-
mophenylboronic acid (2d), 4-chlorophenylboronic acid
(2e), 4-fluorophenylboronic acid (2f), and 4-(trifluorome-
thyl)phenylboronic acid (2g) reacted with 1a to afford
3ad, 3ae, 3af, and 3ag in 70%, 82%, 87%, and 60%
yields, respectively (Table 3, entries 4–7). Moreover, 1-
naphthylboronic acid (2h) and 2-naphthylboronic acid
(2i) also gave the corresponding diaryl ketones 3ah and
3ai in 71% and 65% yields, respectively (Table 3, entries
8 and 9). On the other hand, the products of 3ad and 3eb
had the bromo group untouched, showed high selectivity
(Table 3, entries 4 and 13).
CsF
xylene
DMF
9
<5
<5
<5
CsF
CsF
DMSO
NMP
CsF
a Reaction conditions: 1a (0.3 mmol), 2a (0.6 mmol), base (0.9
mmol), Cu(OAc)2·H2O (10 mol%), additive (0.1 mmol), dppf (10 mol
%) air, solvent (2 mL), 120 °C, 24 h.
b Isolated yield.
gen ligands (Scheme 1, L18–L23) which had no activity
except for ligands L16 and L17. Finally, we chose the
commercially available L13 as the best ligand for our sys-
tem.
Encouraged by this promising result, we further optimized
the reaction conditions, such as bases, copper source, and
ratio of L13/Cu for phenylation of 4-nitrobenzaldehyde,
and the results are listed in Table 2. Among the bases,
KF·2H2O was superior to some others such as NaOAc,
K2CO3, Cs2CO3, and CsOH·H2O (Table 2, entries 1–5).
Then using KF·2H2O as the base we screened the influ-
ence of the copper sources, Cu(OTf)2 exhibited the high-
est catalytic activity compared with Cu(OAc)2·H2O,
CuBr2, CuCl2, CuF2, CuBr, CuCl, and Cu2O, affording a
70% yield (Table 2, entries 5–12). Decreasing the amount
of KF·2H2O to 2.0 equivalents increased the yield to 73%
(Table 2, entry 17). Increasing the ratio of Cu/L13 or de-
creasing the ratio of Cu/L13 in the system reduced the
yield slightly (Table 2, entries 13–15). To our delight, the
As shown in Table 3, the influence of a monosubstituent
group at the ortho, meta, and para position for both aryl-
boronic acids (Table 3, entries 1–3) and aromatic alde-
hydes (Table 3, entries 1, 10, and 11) was investigated to
examine the steric effect in our system. For example, 2b
proceeded with aldehydes 1a, 1b, and 1c efficiently and
3ab, 3bb, and 3cb were obtained in 86%, 88%, and 89%
Synlett 2011, No. 11, 1626–1630 © Thieme Stuttgart · New York

1628
H. Zheng et al.
LETTER
Table 2 Effects of Base, Cu Source, and L13/Cu Ratioa
tries 19–21). However, treatment of an alkylboronic acid
such as cyclopropylboronic acid (2k) with p-nitrobenzal-
dehyde under the optimized conditions, the desired prod-
uct 3ak was obtained in 19% yield (Table 3, entry 22).
O
Cu source, Xantphos
O2N
CHO
+
PhB(OH)2
O2N
base, toluene
Ph
1a
2a
3aa
Table 3 Substrate Scope in the Copper-Catalyzed Arylation of
Entry Cu source
Base (equiv)
L13/Cu ratio Yield (%)b
Arylboronic Acids with Aldehydesa
1
2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
CuBr2
NaOAc (3)
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
0.5
1
<5
52
<5
<5
57
<5
<5
<5
56
<5
<5
70
20
48
53
50
73
85c
O
CHO
Cu(OTf)2, Xantphos
Ar
K2CO3 (3)
+
ArB(OH)2
R
R
KF, toluene
3
Cs2CO3 (3)
1
2
3
4
CsOH·H2O (3)
KF·2H2O (3)
KF·2H2O (3)
KF·2H2O (3)
KF·2H2O (3)
KF·2H2O (3)
KF·2H2O (3)
KF·2H2O (3)
KF·2H2O (3)
KF·2H2O (3)
KF·2H2O (3)
KF·2H2O (3)
KF·2H2O (1)
KF·2H2O (2)
KF·2H2O (2)
Entry Aldehyde
Boronic acid
Product Yield
(%)b
5
6
B(OH)2
O2N
CHO
1
3aa
3ab
85
86
7
CuCl2
1a
2a
8
CuF2
B(OH)2
2
3
1a
9
CuBr
2b
10
11
12
13
14
15
16
17
18
CuCl
1a
3ac
72
B(OH)2
Cu2O
2c
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Br
B(OH)2
4
5
6
7
1a
1a
1a
1a
3ad
3ae
3af
3ag
70
82
87
60
2d
2
Cl
B(OH)2
B(OH)2
B(OH)2
1.5
1.5
1.5
1.5
2e
F
2f
F3C
a Reaction conditions: 1a (0.3 mmol), 2a (0.6 mmol), base, Cu source
(10 mol %), air, toluene (2 mL), 120 °C, 24 h.
b Isolated yield.
2g
c The reaction was run under an oxygen atmosphere.
8
1a
1a
3ah
71
B(OH)2
2h
yields, respectively (Table 3, entries 2, 10, and 11), dem-
onstrating little steric effect on the yields in the reaction.
9
10
11
3ai
65
88
89
For the aldehydes, electron-withdrawing and electron-
rich aromatic aldehydes reacted with 2b and gave diaryl
ketones (3bb–jb) with moderate to good yields (Table 3,
entries 10–18). Aldehydes such as 1e, 1f, and 1g reacted
well with 2a, and the products 3ea, 3fa, and 3ga were iso-
lated in 88%, 67%, and 61% yields, respectively (Table 3,
entries 13–15).
B(OH)2
2i
NO2
2b
3bb
3cb
CHO
1b
2b
O2N
CHO
Aldehydes containing a strongly electron-withdrawing
group, such as 4-(methylsulfonyl)benzaldehyde (1d) and
2,4-dinitrobenzaldehyde (1h) afforded the corresponding
diaryl ketones 3db22 and 3hb in 67% and 63% yields, re-
spectively (Table 3, entries 12 and 16). Benzaldehyde (1i)
and 4-methylbenzaldehyde (1j) coupled with 2b to afford
3ib and 3jb in 60% and 75% isolated yields, respectively
(Table 3, entries 17 and 18). Unfortunately, the reaction
was unsuccessful using aldehydes with a heteroatom, ali-
phatic aldehydes, and heteroarylboronic acid (Table 3, en-
1c
O
S
Me
CHO
12
13
2b
2b
3db
3eb
67
88
O
1d
Br
CHO
1e
Synlett 2011, No. 11, 1626–1630 © Thieme Stuttgart · New York

LETTER
Copper-Catalyzed Arylation of Arylboronic Acids with Aldehydes
1629
Table 3 Substrate Scope in the Copper-Catalyzed Arylation of
References and Notes
Arylboronic Acids with Aldehydesa (continued)
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CHO
Cu(OTf)2, Xantphos
Ar
+
ArB(OH)2
R
R
KF, toluene
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2
3
Entry Aldehyde
Boronic acid
Product Yield
(%)b
Cl
CHO
CHO
14
2b
2b
3fb
67
61
1f
F
15
3gb
1g
O2N
NO2
16
2b
3hb
63
CHO
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1h
CHO
17
18
2b
2b
3ib
3jb
60
75
1i
1j
CHO
19
20
2b
2b
3kb
3lb
trace
trace
CHO
O
1k
n-C9H19CHO
1l
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21
22
1a
1a
3aj
trace
19
B(OH)2
O
2j
B(OH)2
3ak
2k
a Reaction conditions: 1 (0.3 mmol), 2 (0.6 mmol), Cu(OTf)2 (10
mol%), Xantphos (15 mol%), KF·2H2O (0.6 mmol), toluene (2 mL),
120 °C, 24 h, O2 atmosphere.
b Isolated yields.
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arylboronic acids in the presence of Cu(OTf)2 and Xant-
phos under oxygen atmosphere. Work to probe the de-
tailed mechanism and apply the reaction in organic
synthesis is currently under way in our laboratory.
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Acknowledgment
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We thank the National Natural Science Foundation of China (No.
21072153), the Wenzhou Technology Bureau Program (No.
G20090076), and the Science and Technology Department of
Zhejiang Province (No. 2009R50002 and 2011R09002-03) for fi-
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Synlett 2011, No. 11, 1626–1630 © Thieme Stuttgart · New York

1630
H. Zheng et al.
LETTER
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(22) General Procedure for the Synthesis of Diaryl Ketones
Under nitrogen atmosphere, a Schlenk tube was charged
with aldehyde (0.3 mmol), arylboronic acid (0.6 mmol),
Cu(OTf)2 (10 mol%), Xantphos ligand (15 mol%), and
KF·2H2O (0.6 mmol) in toluene (2 mL) under ice-salt
(–20 °C). The mixture was stirred for 6 h at r.t. under
nitrogen atmosphere. Then pass into the oxygen, the mixture
was stirred for 0.5 h at r.t. and heated up to reflux
temperature (about 120 °C) for 24 h under oxygen
atmosphere. After the completion of the reaction, as
monitored by TLC, the solvent was concentrated in vacuo,
and the residue was purified by flash column chromatog-
raphy on silica gel (300–400 mesh) with PE–EtOAc as
eluent to give the desired product.
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Naphthalen-2-yl(4-nitrophenyl)methanone (3ai, Table 3,
Entry 9)
1H NMR (300 MHz, CDCl3): d = 7.57–7.69 (m, 2 H), 7.91–
8.00 (m, 6 H), 8.23 (s, 1 H), 8.22–8.40 (m, 2 H). 13C NMR
(125 MHz, CDCl3): d = 123.6, 125.2, 127.2, 127.9, 128.8,
129.0, 129.5, 130.7, 132.1, 132.4, 133.5, 135.6, 143.2,
149.8, 194.8. ESI-MS: m/z (%) = 278 (100) [M + 1]+. Anal.
Calcd for C17H11NO3: C, 73.64; H, 4.00. Found: C, 73.66; H,
4.05.
4-Methylsulfonylphenyl(4-tolyl)methanone (3db,
Table 3, Entry 12)
1H NMR (300 MHz, CDCl3): d = (s, 3 H), 3.12 (s, 3 H), 7.32
(d, J = 8.1 Hz, 2 H), 7.71 (d, J = 8.1 Hz, 2 H), 7.93 (d, J = 8.4
Hz, 2 H), 8.06 (d, J = 8.4 Hz, 2 H). 13C NMR (125 MHz,
CDCl3): d = 21.7, 44.4, 127.4, 129.3, 130.3, 133.7, 142.7,
143.2, 144.5, 194.8. ESI-MS: m/z (%) = 275 (100) [M + 1]+.
Anal. Calcd for C15H14O3S: C, 65.67; H, 5.14. Found: C,
65.82; H, 5.22.
2,6-Dinitrophenyl(4-tolyl)methanone (3hb, Table 3,
Entry 16)
1H NMR (300 MHz, CDCl3): d = (s, 3 H), 7.29 (d, J = 8.1
Hz, 2 H), 7.63 (d, J = 8.1 Hz, 2 H), 7.70 (d, J = 8.1 Hz, 2 H),
8.62 (d, J = 8.1 Hz, 2 H), 9.08 (s, 1 H). 13C NMR (125 MHz,
CDCl3): d = 21.8, 120.1, 128.4, 129.6, 129.8, 130.3, 132.4,
141.7, 146.0, 146.0, 148.4, 190.9. MS (EI): m/z (%) = 287
(100) [M + 1]+. Anal. Calcd for C14H10N2O5: C, 58.74; H,
3.52. Found: C, 58.83; H, 3.63.
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Maseras, F. J. Organomet. Chem. 2006, 691, 4459.
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Walker, S. D.; Martinelli, J. R.; Buchwald, S. L. J. Am.
Chem. Soc. 2005, 127, 4685. (d) Littke, A. F.; Fu, G. C.
Synlett 2011, No. 11, 1626–1630 © Thieme Stuttgart · New York