Cationic Pd(II)/bipyridine-catalyzed addition of arylboronic acids to arylaldehydes. One-pot synthesis of unsymmetrical triarylmethanes

Article abstract of DOI:10.1021/jo071232k

(Chemical Equation Presented) Cationic Pd(II) complex-catalyzed addition of arylboronic acids to aldehydes with low catalyst loading was developed with high yields. One-pot synthesis of unsymmetrical triarylmethanes from arylboronic acids, aryl aldehydes, and electron-rich arenes was achieved in high yields.

Full text of DOI:10.1021/jo071232k

SCHEME 1. Proposed Mechanism for the Addition of
Arylboronic Acids to Arylaldehydes Catalyzed by Catalyst
A2
Cationic Pd(II)/Bipyridine-Catalyzed Addition of
Arylboronic Acids to Arylaldehydes. One-Pot
Synthesis of Unsymmetrical Triarylmethanes
Shaohui Lin and Xiyan Lu*
State Key Laboratory of Organometallic Chemistry, Shanghai
Institute of Organic Chemistry, Chinese Academy of Sciences,
354 Fenglin Lu, Shanghai 200032, China
xylu@mail.sioc.ac.cn
ReceiVed June 20, 2007
Cationic Pd(II) complex-catalyzed addition of arylboronic
acids to aldehydes with low catalyst loading was developed
with high yields. One-pot synthesis of unsymmetrical tri-
arylmethanes from arylboronic acids, aryl aldehydes, and
electron-rich arenes was achieved in high yields.
formed by the acetoxypalladation of the alkynes, to R,â-
unsaturated carbonyl compounds,6d,e ketones,6f and nitriles.6f It
was suggested that the electron-donating property of the ligands
would make the organopalladium species more nucleophilic,
and would favor the nucleophilic addition.3,4 On the basis of
this suggestion, we successfully developed the Pd(II)/bpy-
catalyzed addition of arylboronic acids to R,â-unsaturated
carbonyl compounds7a and nitriles7b with high yields and also
the cationic Pd(II)/bpy-catalyzed one-step synthesis of benzo-
furans from phenoxyacetonitriles.8a In all these reactions, bpy
was used as the ligand making the nucleophilic addition of
arylboronic acids to carbon-heteroatom multiple bonds suc-
cessful. It was also found that the cationic Pd(II) species with
chiral phosphine ligand could catalyze the intramolecular
addition of arylboronic acids to ketones with excellent yields
and high ee values.8b These examples showed that cationic Pd-
(II) complexes are excellent catalysts for the addition of
arylboronic acids to carbon-heteroatom multiple bonds due to
their high Lewis acidity and existence of vacant coordination
sites.8
Transition metal catalysis provides powerful tools for carbon-
carbon bond construction.1 Recent reports on Rh(I)-catalyzed
addition reactions of arylboronic acids to various electrophiles2
prompted us to examine the Pd(II)-catalyzed nucleophilic
addition reactions of arylboronic acids. Compared with numer-
ous reports of Rh(I)-catalyzed addition reactions to aldehydes,
ketones, imines, and nitriles, Pd(II)-catalyzed nucleophilic
addition reactions of arylboronic acids are relatively rare.3 While
arylrhodium species are more nucleophilic and capable of
addition to electrophiles, arylpalladium species are more elec-
trophilic.4 For the palladium catalysts, it is worth mentioning
that Miyaura reported the conjugate addition of arylboronic acids
to enones catalyzed by cationic Pd(II) complex with phosphine
ligands.5a,b In our previous work, we found that bidentate
nitrogen ligands such as 2,2′-bipyridine (bpy), phenanthroline,
and dioxazolines could stabilize the Pd(II) species.6 We reported
the Pd(II)/bpy-catalyzed addition of alkenylpalladium species,
(1) (a) de Meijere, A.; Diederich, F. Metal-Catalyzed Cross-Coupling
Reactions, 2nd ed.; Wiley-VCH: Weinheim, Germany, 2004. (b) Beller,
M.; Bolm, C. Transition Metals for Organic Synthesis: Building Blocks
and Fine Chemicals; Wiley-VCH: New York, 1998.
Miyaura reported the first Rh(I)-catalyzed addition of aryl-
boronic acids to aldehydes9a,b and the asymmetric version of
this reaction with moderate ee values has been reported by some
(2) (a) Fagnou, K.; Lautens, M. Chem. ReV. 2003, 103, 169. (b) Hayashi,
T.; Yamasaki, K. Chem. ReV. 2003, 103, 2829.
(3) Yamamoto, Y.; Nishikata, T.; Miyaura, N. J. Synth. Org. Chem., Jpn.
2006, 64, 1112.
(7) (a) Lu, X.; Lin, S. J. Org. Chem. 2005, 70, 9651. (b) Zhao, B.; Lu,
X. Tetrahedron Lett. 2006, 47, 6765.
(4) Ueura, K.; Satoh, T.; Miura, M. Org. Lett. 2005, 7, 2229.
(5) (a) Nishikata, T.; Yamamoto, Y.; Miyaura, N. Angew. Chem., Int.
Ed. 2003, 42, 2768. (b) Nishikata, T.; Yamamoto, Y.; Miyaura, N.
Organometallics 2004, 23, 4317.
(6) (a) Lu, X. Top. Catal. 2005, 35, 75. (b) Zhang, Q.; Lu, X. J. Am.
Chem. Soc. 2000, 122, 7604. (c) Zhang, Q.; Lu, X.; Han, X. J. Org. Chem.
2001, 66, 7676. (d) Zhao, L.; Lu, X. Org. Lett. 2002, 4, 3903. (e) Zhao, L.;
Lu, X.; Xu, W. J. Org. Chem. 2005, 70, 4059. (f) Zhao, L.; Lu, X. Angew.
Chem., Int. Ed. 2002, 41, 4343.
(8) (a) Zhao, B.; Lu, X. Org. Lett. 2006, 8, 5987. (b) Liu, G.; Lu, X. J.
Am. Chem. Soc. 2006, 128, 16504.
(9) (a) Sakai, M.; Ueda, M.; Miyaura, N. Angew. Chem., Int. Ed. 1998,
37, 3279. (b) Ueda, M.; Miyaura, N. J. Org. Chem. 2000, 65, 4450. (c)
Moreau, C.; Hague, C.; Weller, A. S.; Frost, C. G. Tetrahedron Lett. 2001,
42, 6957. (d) Fuchen, T.; Rudolph, J.; Bolm, C. Synthesis 2005, 429. (e)
Duan, H.; Xie, J.; Shi, W.; Zhang, Q.; Zhou, Q. Org. Lett. 2006, 8, 1479.
(f) Jagt, R. B. C.; Toullec, P. Y.; de Vries, J. G.; Feringa, B. L.; Minnaard,
A. J. Org. Biomol. Chem. 2006, 4, 773.
10.1021/jo071232k CCC: $37.00 © 2007 American Chemical Society
Published on Web 11/14/2007
J. Org. Chem. 2007, 72, 9757-9760
9757

TABLE 1. Cationic Pd(II)-Catalyzed Addition of Phenylboronic
Acid to 4-Nitrobenzaldehydea
TABLE 3. Cationic Pd(II) Complex A2-Catalyzed Addtion of
Arylboronic Acids to Aldehydesa
entry
catalyst
solvent
time (h)
yield (%)b
1
2
3
4
5
6
7
8
9
Pd(OAc)2/bpy
A1
Pd(OAc)2/bpy
A1
A1
A1
A1
A1
A1
A1
HOAc/THF/H2O
CH3NO2
CH3NO2
dioxane
DMSO
DMF
HMPA
toluene
cyclohexane
CH3NO2
24
0.7
24
24
24
24
24
24
24
0.7
trace
95
98
98
0
trace
0
0
0
10
98c
a Reaction conditions: PhB(OH)2 (0.50 mmol), 4-nitrobenzaldehyde (0.25
mmol), cationic Pd(II) complex A1 (2.5 mol %), CH3NO2 (0.5 mL) in a
sealed tube at 80 °C. b Isolated yield. c PhB(OH)2 (0.30 mmol, 1.2 equiv).
TABLE 2. Effect of the Counter Anions of Cationic Pd(II)
Complexes and the Catalyst Loadinga
entry
anion, X-
temp (oC)
time (h)
yield (%)b
1
2
3
4
5
6
7
8
BF4 - (A2)
OTf - (A1)
NO3 - (A3)
BF4 - (A2)
OTf - (A1)
NO3 - (A3)
BF4 - (A2)
BF4 - (A2)
25
25
25
50
50
50
50
50
1.5
4
36
1
99
87c
96
96
99
3
24
10
48
96
99d
99e
a Reaction conditions: PhB(OH)2 (0.12 mmol), 4-nitrobenzaldehyde (0.10
mmol), cationic Pd(II) complex (0.0025 mmol, 2.5 mol %), CH3NO2 (0.3
mL) in a sealed tube. b Isolated yield. c The yield was not increased for a
longer reaction time. d PhB(OH)2 (0.60 mmol), 4-nitrobenzaldehyde (0.50
mmol), cationic Pd(II) complex A2 (0.5 mol %). e PhB(OH)2 (1.2 mmol),
4-nitrobenzaldehyde (1.0 mmol), cationic Pd(II) complex A2 (0.25 mol %).
a Reaction conditions: ArB(OH)2 (0.60 mmol), aldehyde (0.50 mmol),
cationic Pd(II) complex A2 (0.5 mol %), CH3NO2 (0.3 mL), 50 °C. b Isolated
yield. c 2.5 mol % of Pd catalyst A2 at 25 °C, prolonged time made the
reaction disordered. d 2.5 mol % of Pd catalyst A2, room temperature.
was used in CH3NO2, the reaction also afforded 1 in 98% yield
but a prolonged time was required (Table 1, entry 3). The
reaction rate was slower when the reaction was carried out in
dioxane, but 98% yield of product was still obtained after 24 h
(Table 1, entry 4). In the other polar solvents such as DMSO,
DMF, and HMPA, and nonpolar solvents such as toluene and
cyclohexane, the reaction can hardly proceed (Table 1, entries
5-9). The cationic Pd(II) complex A1 is insoluble in nonpolar
solvent, and the polar solvent molecules with high coordinating
ability might occupy the vacant coordination site of cationic
Pd(II) complexes. Thus, CH3NO2 is the better choice as the
solvent. The nearly quantitative yield was still maintained when
the amount of phenylboronic acid was decreased to 1.2 equiv
(Table 1, entry 10).
groups.9a,c-f To the best of our knowledge, only a few works10
were reported with use of Pd catalyst for this reaction. Herein,
we wish to report the cationic Pd(II)/bpy-catalyzed addition of
arylboronic acids to aldehydes.
First, we tried the addition of phenylboronic acid to 4-ni-
trobenzaldehyde using our previously reported optimized condi-
tions for conjugate addition. Only trace amounts of the desired
product 1 were detected (Table 1, entry 1). The success of the
catalysis of cationic Pd(II) complex A1 with bpy ligands for
the addition of arylboronic acids to nitriles8a prompted us to
use A1 as the catalyst for this reaction. To our surprise, 95% of
the addition product 1 was isolated in CH3NO2 at 80 °C after
40 min (Table 1, entry 2). When the neutral palladium catalyst
The effect of different counter anoins of Pd(II) complexes
-
was also examined. With BF4 as the anion, the reaction was
completed at room temperature in 1.5 h affording 99% yield
(Table 2, entry 1). For OTf-, the aldehyde could not be
completely converted at room temperature (Table 2, entry 2).
As for NO3-, the yield was also excellent but the rate was slower
(Table 2, entry 3). Higher temperature sped up the reaction and
(10) (a) Yamamoto, T.; Ohta, T.; Ito, Y. Org. Lett. 2005, 7, 4153. (b)
Suzuki, K.; Arao, T.; Ishii, S.; Maeda, Y.; Kondo, K.; Aoyama, T.
Tetrahedron Lett. 2006, 47, 5789. (c) He, P.; Lu, Y.; Dong, C.-G.; Hu,
Q.-S. Org. Lett. 2007, 9, 343. (d) During the preparation of this manuscript,
we found: Qin, C.; Wu, H.; Cheng, J.; Chen, X.; Liu, M.; Zhang, W.; Su,
W.; Ding, J. J. Org. Chem. 2007, 72, 4102.
9758 J. Org. Chem., Vol. 72, No. 25, 2007

TABLE 4. Condition Optimization of the One-Pot Synthesis of
Unsymmetrical Triarylmethanesa
TABLE 5. Cationic Pd(II) Complex A2-Catalyzed One-Pot
Synthesis of Unsymmetrical Triarylmethanesa
arene/aldehyde
(molar ratio)
entry
anion X-
time (h)
yield (%)c
1b
2
3
4
5
6
7
8
9
1.0
1.0
1.0
1.0
1.0
2.0
2.0
2.0
2.0
OTf - (A1)
OTf - (A1)
OTf - (A1)
OTf - (A1)
OTf - (A1)
OTf - (A1)
NO3 - (A3)
BF4 - (A2)
BF4 - (A2)
8
4
21d
40d
52
24
24
24
24
24
24
24
40e
tracef
84
40
92
96g
a Reaction conditions: PhB(OH)2 (0.20 mmol), aldehyde (0.10 mmol),
1,3,5-trimethoxybenzene, cationic Pd(II) complex (2.5 mol %), CH3NO2
(0.3 mL), 80 °C. b Reaction conditions: PhB(OH)2 (0.20 mmol), aldehyde
(0.10 mmol), cationic Pd(II) complex (2.5 mol %), and CH3NO2 (0.3 mL)
were first reacted at 80 °C, 1,3,5-trimethoxybenzene was added after the
completion of the first step. c Isolated yield. d The yield was not increased
for a longer reaction time. e Addition of 3 Å MS (10 mg). f Addition of
H2O (0.05 mL). g PhB(OH)2 (0.12 mmol).
-
the yields were excellent (Table 2, entries 4-6). Thus BF4
was chosen as the optimized anion. Cationic Pd(II) complex
A2 is highly effective for addition of arylboronic acids to
aldehydes. Nearly quantitative yields were still maintained even
when the catalyst loading was decreased to 0.5 or 0.25 mol %
(Table 2, entries 7 and 8). Thus, PhB(OH)2 (0.60 mmol),
aldehyde (0.50 mmol), cationic Pd(II) complex A2 (0.0025
mmol, 0.5 mol %), and CH3NO2 (0.3 mL) in a sealed tube at
50 °C were chosen as the optimized conditions.
The scope of the reaction with different aromatic aldehydes
is outlined in Table 3. For aldehydes with electron-withdrawing
groups, good to nearly quantitative yields were obtained (Table
3, entries 1-8). While the electron-withdrawing groups (e.g.,
nitro-, chloro-, and bromo-substituents) of arylaldehydes are not
tolerated in the reaction with Grignard reagents or the organo-
lithium reagents,11 the tolerance of these electron-withdrawing
groups is the advantage of this reaction. When benzaldehyde
and electron-donating aldehydes were used in the reaction, the
yields dropped (Table 3, entries 9 and 10). For anisaldehyde,
the reaction was disordered at 50 °C. When 2.5 mol % of Pd-
(II) catalyst was loaded at room temperature, only 14% of
desired product was isolated after 5 h (Table 3, entry 11). Also
the influence of different arylboronic acids was examined. The
reaction of p-methoxyphenylboronic acid in 50 °C also gave a
mixture of products, but the reaction afforded nearly quantitative
yield of addition product after 1 h when 2.5 mol % of Pd(II)
catalyst A2 was loaded at room temperature (Table 3, entry
12). For the other arylboronic acids tested, good to excellent
yields of addition products were isolated (Table 3, entries 13-
16).
a Reaction conditions: ArB(OH)2 (0.12 mmol), ArCHO (0.10 mmol),
1,3,5-trimethoxybenzene (0.20 mmol), cationic Pd(II) complex A2 (2.5 mol
%), CH3NO2 (0.3 mL), 80 °C. b Isolated yield. c 1,4-Dimethoxybenzene
(0.20 mmol) was used as the third component.
A plausible mechanism for the cationic palladium-catalyzed
addition of arylboronic acids to arylaldehydes is shown in
Scheme 1. First, transmetalation between arylboronic acid and
palladium catalyst yields the arylpalladium species I, followed
by the coordination of the arylaldehyde giving II. Addition of
the carbon-palladium bond to the carbonyl group yields
diarylmethoxypalladium species III. Transmetalation of III with
arylboronic acid followed by protonolysis gives the addition
product and regenerates the species I.9f With these results in
hand, a new application of this reaction was tried. When PhB-
(OH)2, 4-nitrobenzaldehyde, and 1,3,5-trimethoxybenzene were
mixed in above standard conditions, an unsymmetrical triaryl-
methane, (p-nitrophenyl)-(2,4,6-trimethoxyphenyl)phenylmethane
(17), was isolated in 21% yield. In the well-studied Lewis acid-
catalyzed Friedel-Crafts addition of electron-rich arenes to
aldehydes or imines, symmetrical triarylmethanes were generally
produced,12a-h but few examples of one-pot synthesis of
(11) Larock, R. C. ComprehensiVe Organic Transformations: A Guide
to Functional Preparations, 2nd ed.; Wiley-VCH: New York, 1999.
J. Org. Chem, Vol. 72, No. 25, 2007 9759

SCHEME 2. Possible Pathway of the Formation of
Unsymmetrical Triarylmethanes
In conclusion, we developed a cationic Pd(II)/bpy-catalyzed
addition of arylboronic acids to aldehydes with low catalyst
loading and high yields in mild conditions. A molecule
containing three kinds of aryl rings with different electron
density can be constructed in one pot and a convenient synthesis
of unsymmetrical triarylmethanes was developed.
Experimental Section
General. All solvents were dried and distilled before use
according to the standard methods. All melting points were
uncorrected.
unsymmetrical triarylmethanes were reported.12e In our reaction,
a molecule containing three kinds of aryl rings with different
electronic characteristics can be constructed in one pot. Inspired
by this result, we began to survey the reaction conditions. The
optimization results are summarized in Table 4.
Procedure for the Addition of Phenylboronic Acid to 4-Ni-
trobenzaldehyde. Phenylboronic acid (73 mg, 0.60 mmol), 4-ni-
trobenzaldehyde (76 mg, 0.50 mmol), cationic Pd(II) complex A2
(1.7 mg, 0.0025 mmol, 0.5 mol %), and CH3NO2 (0.4 mL) were
mixed in a sealed tube. The tube was sealed and the mixture was
stirred and heated at 50 °C for 10 h until the substrate disappeared
as monitored by TLC. The reaction mixture was concentrated under
reduced pressure. The residue was purified by flash chromatography
(EtOAc:petroleum ether 1:5) to give the product 1 (114 mg, 0.50
mmol) with 99% yield as a light yellow oil.13 Mp 70-71 °C (lit.13
Our strategy of optimization was to carry this reaction in one
pot with two steps. 1,3,5-Trimethoxybenzene was added after
PhB(OH)2 reacted with aldehyde completely in half an hour.
After 4 h, 40% of triarylmethane was obtained, and prolonged
time gave higher yields (Table 4, entries 2 and 3). While the
addition of water stopped the reaction completely (Table 4, entry
5), the addition of 3 Å MS did not help the reaction (Table 4,
entry 4). Then 2.0 equiv of 1,3,5-trimethoxybenzene was added
and the yield was improved to 84% (Table 4, entry 6). For
1
mp 72 °C); H NMR (300 MHz, CDCl3) δ 8.20 (d, J ) 8.7 Hz,
2H), 7.59 (d, J ) 8.7 Hz, 2H), 7.41-7.29 (m, 5H), 5.93 (d, J )
3.3 Hz, 1H), 2.38 (d, J ) 3.3 Hz, 1H); IR (KBr) ν 3500, 1596,
1515, 1344, 707 cm-1; MS (70 eV, EI) m/z (%) 229 (M+), 150,
105, 79, 44 (100).
-
different anions of Pd(II) catalysts, the catalyst with the BF4
Procedure for the Synthesis of (p-Nitrophenyl)(phenyl)(2,4,6-
trimethoxyphenyl)methane (17). Phenylboronic acid (15 mg, 0.12
mmol), 4-nitrobenzaldehyde (15 mg, 0.10 mmol), cationic Pd(II)
complex A2 (1.7 mg, 0.0025 mmol, 5 mol %), and CH3NO2 (0.3
mL) were mixed in a sealed tube. The tube was sealed and the
mixture was stirred and heated at 80 °C for 0.5 h until the substrates
disappeared as monitored by TLC. Then 1,3,5-trimethoxybenzene
(34 mg, 0.20 mmol) was added and the tube was sealed and heated
for 24 h. The reaction mixture was concentrated under reduced
pressure. The residue was purified by flash chromatography
(EtOAc:petroleum ether 1:10) to give the product 17 (36 mg, 0.096
as anion was proved to be the best (Table 4, entry 8). When
the PhB(OH)2 was decreased to 1.2 equiv, 96% yield of the
product was isolated (Table 4, entry 9).
The results of different arylboronic acids and arylaldehydes
are summarized in Table 5. It was shown that aryl groups with
different electron density of arylboronic acids can be easily
introduced with moderate to excellent yields (Table 5, entries
1-4). Arylboronic acid with electron-donating groups afforded
the highest yield (Table 5, entry 5). Electron-deficient aldehydes
were chosen for their high reactivity. As for electron-rich arenes,
1,3,5-trimethoxybenzene and 1,4-dimethoxybenzene (Table 5,
entry 6) were the appropriate components. Other kinds of arenes,
such as indoles and furans, often lead to complicated results.
When anisole was used in the optimized conditions, no reaction
occurred.
The formation of unsymmetrical triarylmethanes may proceed
via the following pathway (Scheme 2).12e First, arylboronic acids
were added to the carbonyl group of the aldehydes, and
diarylmethanol IV was formed. Then, the hydroxy group of
intermediate IV was activated by the cationic Pd(II) species
and the electron-rich arene was added to IV to yield triaryl-
methane V.
1
mmol) with 96% yield as a light yellow solid. Mp 97-98 °C; H
NMR (300 MHz, CDCl3) δ 8.11-8.02 (m, 2H), 7.34-7.15 (m,
7H), 6.15 (s, 2H), 6.09 (s, 1H), 3.81 (s, 3H), 3.61 (s, 6H); 13C
NMR (75 MHz, CDCl3) δ 160.5, 158.8, 153.1, 145.7, 142.0, 129.5,
129.1, 128.0, 126.1, 122.7, 111.7, 91.3, 55.5, 55.3, 45.2; IR (KBr)
ν 2935, 2839, 1605, 1593, 1515, 1452, 1345, 1224, 1114, 812, 701
cm-1; MS (70 eV, EI) m/z (%) 380 (M+ + 1), 379 (M+, 100), 302,
257, 149, 91, 71, 43. HRMS calcd for C22H21NO5 379.1420, found
379.1420.
Acknowledgment. The authors thank the Major State Basic
Research Program (2006CB806105). We also thank the National
Natural Sciences Foundation of China (20423001) and the
Chinese Academy of Sciences for financial support.
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Supporting Information Available: Typical experimental
procedure and characterization data of all products. This material
is available free of charge via the Internet at http://pubs.acs.org.
JO071232K
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9760 J. Org. Chem., Vol. 72, No. 25, 2007