One-pot synthesis of diaryl ketones from aldehydes via palladium-catalyzed reaction with aryl boronic acids

Article abstract of DOI:10.1016/j.tetlet.2007.12.074

A Pd-catalyzed coupling-type reaction of aldehydes and organoboronic acids was achieved in the presence of P(1-nap)₃, using Cs₂CO₃ in toluene, providing diaryl ketones with yields ranged from moderate to excellent. The efficiency of this reaction was demonstrated by the compatibility with nitro, cyano, trifluoromethyl, fluoro and chloro groups. Moreover, the rigorous exclusion of air/moisture is not required in these transformations.

Full text of DOI:10.1016/j.tetlet.2007.12.074

Available online at www.sciencedirect.com
Tetrahedron Letters 49 (2008) 1884–1888
One-pot synthesis of diaryl ketones from aldehydes via
palladium-catalyzed reaction with aryl boronic acids
a
a
a,
a,
a
*
*
Changming Qin , Jiuxi Chen , Huayue Wu , Jiang Cheng , Qiang Zhang ,
Bing Zuo a, Weike Su a,b, Jinchang Ding a
a College of Chemistry and Materials Science, Wenzhou University, Wenzhou 325027, PR China
b College of Pharmaceutical Sciences, Zhejiang University of Technology, Zhejiang Key Laboratory of Pharmaceutical Engineering,
Hangzhou 310014, PR China
Received 23 September 2007; revised 11 December 2007; accepted 14 December 2007
Available online 23 December 2007
Abstract
A Pd-catalyzed coupling-type reaction of aldehydes and organoboronic acids was achieved in the presence of P(1-nap)3, using Cs2CO3
in toluene, providing diaryl ketones with yields ranged from moderate to excellent. The efficiency of this reaction was demonstrated by
the compatibility with nitro, cyano, trifluoromethyl, fluoro and chloro groups. Moreover, the rigorous exclusion of air/moisture is not
required in these transformations.
Ó 2007 Published by Elsevier Ltd.
Keywords: Diarylketone; One-pot; Aldehyde; Arylboronic acid; Palladium-catalyzed
Diaryl and aryl-alkyl ketones are important building
blocks in the synthesis of natural products and pharmaco-
logical compounds as well as material science target mole-
cules.1 General methods for the preparation of these
compounds include Friedel–Crafts acylation reactions,2
and acylation of organometallic reagents reactions.3 How-
ever, these methods suffer from their lack of atom economy
due to the use of a stoichiometric amount of aluminum tri-
chloride or anhydrous conditions required for both part-
ners. Alternative transformations used to construct these
diaryl ketones involve the metal-catalyzed coupling reac-
tions of carboxylic anhydrides,4 esters,5 thiol esters6 with
organometallic compounds. These reports, nevertheless,
had a limited substrate scope or might need the additives.
Some other approaches involve a metal-catalyzed reaction
between aryl halide and an aldehyde or its derivative.
Hartwig and co-workers reported a rhodium-catalyzed
coupling of aryl iodides with N-pyrazyl aldimines7 and a
palladium-catalyzed coupling of aryl bromides with
N-tert-butylhydrazones.8 The formation of ketones by this
methods required two steps and strong base NaOBut. Aryl
iodides coupled with aldehydes in the presence of Ni(dp-
pe)Br2 and Zn to give the corresponding biaryl ketones have
also been described by Cheng and co-workers.9 Cooperative
catalysis by Ru and Pd for the direct coupling of achelating
aldehyde with iodoarenes or organostannanes was reported
by Chang and co-workers.10 The high availability of alde-
hydes renders this route particularly attractive.
Recently, Genet and co-workers have reported direct
access to ketones from aldehydes via rhodium-catalyzed
cross-coupling reaction with potassium tifluoro(organo)-
borates.11 To the best of our knowledge, one-pot synthesis
diaryl ketones from aldehydes by palladium-catalyzed reac-
tion with organoboronic acids have been unexplored ever
before.
*
Corresponding authors. Tel./fax: +86 577 88368280 (H.W.); tel./fax:
+86 577 88156826 (J.C.).
Recent studies in our group have focused on extending
the scope and utility of the reaction between organoboron
E-mail addresses: huayuewu@wzu.edu.cn (H. Wu), jiangcheng@
wzu.edu.cn (Q. Zhang).
0040-4039/$ - see front matter Ó 2007 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2007.12.074

C. Qin et al. / Tetrahedron Letters 49 (2008) 1884–1888
1885
reagents and aldehydes. In our previous work, we reported
the combination of PdCl2 and P(1-nap)3 could promote the
arylation of aldehydes to furnish the secondary alcohols in
good to excellent yields at 65 °C Eq. 1.12
ligands (Fig. 1), ratio of L/Pd for phenylation of 4-nitro-
benzaldehyde (Table 2).
As shown in Table 2, PPh3 was totally ineffective in such
transformation. Electron-deficient ligand such as L6 and
bidentate phosphine such as L4 were non effective at all.
Aminophosphine ligands L2 and L3 could improve the
yield to 74% and 68%, respectively. The bulky, electron-
rich monodentate phosphine ligand L5 unexpectedly inhib-
ited the reaction, nevertheless, L1 was tested to be the best
and the yield was dramatically increased to 93% with the
combination of Pd2(dba)3 and L1 (Table 2, entry 12).
Increasing the amount of L1 (Table 1, entries 17, 18) or
decreasing the amount of Cs2CO3 (Table 2, entries 15,
16) in the system reduced the yield slightly.
With optimal conditions in hand, the reaction of differ-
ent organoboronic acids with various aryl aldehydes was
examined to explore the scope of the reaction (Table 3).
As shown in Table 3, the reaction proceeded smoothly
in the presence of a variety of functional groups including
nitro, cyano, acetoxy, trifluoromethyl and chloro groups.
Nitro-substituted aryl aldehydes reacted with arylboronic
acids easily and gave biarylketones in high yield partly
due to the withdrawing group on aryl increased the activity
of C@O bond. Generally, electronically neutral and rich
aldehydes except furan-2-carbaldehyde 2f gave poor yield.
Aliphatic aldehydes have no reactivity at all. Arylboronic
acids with electron-withdrawing substitution group are
prone to homocoupling and protodeboronation side
O
OH
Ar
PdCl2/P(1-Nap)3 5%
K2CO3, THF, 65
H
Ar-B(OH)2
ð1Þ
+
R
R
°
C
3
1
2
Herein, we report an efficient one-pot synthesis of diaryl
ketones from aldehydes via Pd-catalyzed reaction of aryl-
boronic acids, using inorganic base and easily prepared
P(1-nap)3 in common organic solvent, providing aryl-
arylketones with yields ranged from moderate to excellent.
Initial studies focused on the screening of the bases, oxi-
dative additives and solvents using PdCl2 as the palladium
source and P(1-nap)3 as the ligand with the reaction of
phenylboronic acid (1a) and 4-nitrobenzaldehyde (2a) as
the model reaction. The screening results of the bases, addi-
tives and solvents are listed in Table 1.
Through the screening process, no target product was
detected in the presence of a series of oxidative additives;
however, we were delighted to find that the yield could
be improved to 32% when the combination of Cs2CO3
and undried toluene was employed in the air atmosphere.
Encouraged by this promising result, we further optimized
the reaction conditions, such as palladium catalysts,
Table 1
Selected results of bases, additives and solvents screeninga
O
PdCl2 (5 mol %)
P(1-nap)3 (5 mol %)
B(OH)2
+
O2N
CHO
Base, Additive, Solvent
NO2
0.5 mmol
Base (equiv)
1 mmol
Air
Entry
Additive (equiv)
Solvent
Yieldb (%)
1
2
3
4
5
6
7
8
K2CO3 (3)
K2CO3 (3)
K2CO3 (3)
K2CO3 (3)
K2CO3 (2)
K2CO3 (1)
NaOH (3)
KOH (3)
PhI(OAc)2 (1)
Benzoquinone (2)
PCC (1)
Ag2O (3)
NaOH (1)
NaOH (2)
None
THF
THF
THF
THF
THF
THF
THF
THF
<5
<5
<5
<5
<5
8
10
None
<5
<5
<5
<5
<5
<5
<5
<5
<5
<5
<5
<5
32c
9
CsOH (3)
KOBut (3)
Ag2CO3 (3)
None
None
None
None
None
None
None
None
None
None
None
None
THF
THF
THF
10
11
12
13
14
15
16
17
18
19
20
a
Chloroamine-T (3)
Rb2CO3 (3)
Cs2CO3 (3)
Cs2CO3 (3)
Cs2CO3 (3)
Cs2CO3 (3)
Cs2CO3 (3)
Cs2CO3 (3)
Cs2CO3 (3)
Toluene
Dioxane
DMF
DMA
DMSO
BrCH2CH2Br
CH3CH2NO2
THF
Toluene
All of the reaction were run with PdCl2 (5 mol %), P(1-nap)3 (5 mol %) at 65 °C in THF and 120 °C in other solvents in sealed tube for 24 h.
b
c
GC yield.
Isolated yield.

1886
C. Qin et al. / Tetrahedron Letters 49 (2008) 1884–1888
Hetero-aryl boronic acid, such as 1f, was still good
partner in this procedure, albeit the yield was decreased
to 56%, which may be owing to the fact that heteroatom
in the hetero-aryl boronic acid may deactivate the transi-
tion metal.14 Hetero-aryl aldehyde, such as furfural 2f,
had good activity in the reaction, and 3af was isolated
in 71% yield. 4-Chlorophenylboronic acid 1c could pro-
ceed smoothly with 2a to afford 3ca in 75% isolated yield
and keep the chloro group intact. A mono substitution in
the ortho position of the coupling partners reduced reac-
tivity slightly. For example, 3ha and 3ia were isolated in
66% and 65% yield, respectively. Compared with most
of the previous reports, it should be noted that bulky
and cheap aldehydes were relatively excess to the boronic
acids in our system. The feasibility of access to highly hin-
dered diarylketones by use of di-ortho-substituted and
electron-rich 2,6-dimethoxyl-benzaldehyde or mesityl-
boronic acid failed.
P
N
P
N
P
L1
L2
L3
F
F
F
F
F
P
O
P(tBu)2
3
PPh2
PPh2
L4
L5
L6
Fig. 1. Ligands screening.
reactions.13 In our system, however, 1b and le could pro-
ceed smoothly with 2a and 3ba and 3ea were isolated in
91% and 82% yield, respectively (Table 3, entries 7, 10).
O
OH
Toluene, air, refluxing, 24 h
ð2Þ
Cl
Cs2CO3 (3 eq.)
K2CO3 (3 eq.) < 5%
NO2
Cl
NO2
71%
1 mmol
Table 2
Effects of Pd sources, ligands, the amount of base and L/Pd ratio on the palladium-catalyzed phenylation of 4-nitrobenzaldehydea
O
Pd Source, Ligand
B(OH)2
+ O2N
CHO
Cs2CO3, toluene, air
NO2
Entry
Pd source
Base (equiv)
Ligand
L/Pd ratio
Yieldb (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
a
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
PdCl2
PdCl2(PPh3)2
PdCl2(PhCN)2
Pd(PPh3)4
Pd2(dba)3
Pd2(dba)3CHCl3
PdCl2(Py)2
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Cs2CO3 (3)
Cs2CO3 (3)
Cs2CO3 (3)
Cs2CO3 (3)
Cs2CO3 (3)
Cs2CO3 (3)
Cs2CO3 (3)
Cs2CO3 (3)
Cs2CO3 (3)
Cs2CO3 (3)
Cs2CO3 (3)
Cs2CO3 (3)
Cs2CO3 (3)
Cs2CO3 (3)
Cs2CO3 (2)
Cs2CO3 (1)
Cs2CO3 (3)
Cs2CO3 (3)
Cs2CO3 (3)
L1
L2
L3
L4
L5
L6
PPh3
L1
L1
L1
L1
L1
L1
L1
L1
L1
L1
L1
L1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
2
3
1
85
74
68
<5
<5
<5
<5
28
78
73
53
93
83
59
83
81
82
80
86
All reactions were run with 4-nitrobenzaldehyde (151 mg, 1.0 mmol), phenylboronic acid (61 mg, 0.5 mmol), Pd source (5 mol %), Cs2CO3, and
indicated L/Pd ratio in 5 mL undried toluene at 120 °C for 24 h.
b
Isolated yield.

C. Qin et al. / Tetrahedron Letters 49 (2008) 1884–1888
1887
Table 3
Palladium-catalyzed one-pot synthesis of diaryl ketonesa
R1
O
R2
Pd2(dba)3 (2.5 mol %)
P(1-nap)3 (5 mol %)
R1
R2
B(OH)2
+
CHO
Toluene, Cs2CO3, Air
Entry
1
Boronic acids
Aldehydes
O2N
Products
Yieldb (%)
93
1a
2a
3aa
B(OH)2
CHO
O2N
2
3
1a
1a
2b
3ab
3ac
89
42
CHO
2c
CHO
NC
4
5
6
7
1a
1a
1a
2d
CHO
3ad
3ae
3af
3ba
28
72
71c
91
H3COOC
2e
CHO
Cl
O
2f
CHO
1b
B(OH)2
2a
2a
F
8
9
1c
B(OH)2
3ca
3da
75
72
Cl
1d
2a
B(OH)2
B(OH)2
10
11
1e
2a
2a
3ea
3fa
82
56
F3C
S
1f
B(OH)2
B(OH)2
12
13
1g
2a
2a
2a
3ga
3ha
3ia
70
1h
1i
66
B(OH)2
OCH3
B(OH)2
14
65d
a
All reactions were run with aldehyde (1.0 mmol), organoboronic acid (0.5 mmol), Cs2CO3 (488 mg, 1.5 mmol), Pd2(dba)3 (11.4 mg, 2.5 mol %) and L1
(5 mol %, 10.3 mg) in 3 mL undried toluene at 120 °C in sealed tube for 24 h.
b
Isolated yield.
1a 1.0 mmol, 2f 0.5 mmol.
1i 1.0 mmol, 2a 0.5 mmol.
c
d

1888
C. Qin et al. / Tetrahedron Letters 49 (2008) 1884–1888
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found that these secondary alcohols gradually disappeared
during the process of the reaction. Thus we supposed that
in our system Cs2CO3 could mediate the aerobic oxidation
of the addition products formed in situ to aromatic
ketones. To further confirm the supposition, we tested
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reaction.
We found that the corresponding product could be gen-
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Acknowledgments
We thank the National Natural Science Foundation of
China (Nos. 20504023 and 20476098) and Natural Science
Foundation of Zhejiang Province (Nos. Y405015, Y404039
and Y405113) for financial support.
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Supplementary data
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.
2007.12.074.
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