Palladium-catalyzed addition of arylboronic acids to aldehydes

Article abstract of DOI:10.1021/ol051501y

(Chemical Equation Presented) Arylboronic acids react with aldehydes in the presence of a base and a catalytic amount of a palladium(0) complex with chloroform, affording the corresponding secondary alcohols in good yields. General palladium complexes have no catalytic activity without chloroform. Chloroform is essential for this reaction, and palladium complex that was prepared from Pd(PPh₃)₄ with CHCl₃ showed good catalytic acitivty as well.

Full text of DOI:10.1021/ol051501y

ORGANIC
LETTERS
2005
Vol. 7, No. 19
4153-4155
Palladium-Catalyzed Addition of
Arylboronic Acids to Aldehydes
Tetsuya Yamamoto, Tetsuo Ohta,* and Yoshihiko Ito
Department of Molecular Science and Technology, Faculty of Engineering, Doshisha
UniVersity, Kyotanabe, Kyoto 610-0394, Japan
tota@mail.doshisha.ac.jp
Received June 27, 2005
ABSTRACT
Arylboronic acids react with aldehydes in the presence of a base and a catalytic amount of a palladium(0) complex with chloroform, affording
the corresponding secondary alcohols in good yields. General palladium complexes have no catalytic activity without chloroform. Chloroform
is essential for this reaction, and palladium complex that was prepared from Pd(PPh3)4 with CHCl3 showed good catalytic acitivty as well.
The transmetalation between organo-main group metal
reagents and transition metal compounds is an important step
for the generation of active organometallic species in metal-
mediated organic synthesis.1 In general, organoboron reagents
are nontoxic and practically useful for carbon-carbon bond
formations with various electrophiles in the presence of a
transition metal.2 Recently, rhodium-catalyzed carbon-
carbon coupling reactions with organoboron reagents have
been remarkably developed. Miyaura et al. found that
rhodium(I) complexes catalyze 1,2-addition to aldehydes3 and
N-arylsulfonyl aldimines,4 as well as 1,4-addition to R,â-
unsaturated carbonyl compounds with aryl- and 1-alkenyl-
boron compounds.5 Palladium-catalyzed addition reaction of
arylborons was also reported by Uemura, who demonstrated
that palladium(0)-SbCl3 catalyzes the conjugate addition to
R,â-unsaturated carbonyl compounds.6 A cationic palladium-
(II) complex is also usable as an active catalyst for the 1,4-
addition reaction.7 However, unlike the rhodium catalyst, the
palladium complex catalyst provides a rare activity for the
1,2-addition of arylborons to carbon-heteroatom double
bonds. The phosphapalladacyclic complex described by Cole-
Hamilton and co-workers catalyzes the 1,2-addition of
phenylboronic acid to 4-chlorobenzaldehyde.8 Herein, we
report that palladium(0) complexes coordinated by phosphine
ligands catalytically induced 1,2-addition of arylboronic acids
to aldehydes in the presence of base and a catalytic amount
of chloroform (Scheme 1).
Palladium-catalyzed addition of phenylboronic acid to
4-cyanobenzaldehyde was examined,9 and the results are
summarized in Table 1, which shows the effects of palladium
precursors together with phosphine ligands. Pd2(dba)3‚CHCl3
as a palladium(0) precursor catalyzed the 1,2-addition
reaction in the presence of triphenylphosphine. However, the
(1) Beller, M.; Bolm, C. Transition Metals for Organic Synthesis:
Building Blocks and Fine Chemicals; Wiley-VCH: New York, 1998.
(2) For reviews, see: (a) Suzuki, A. Acc. Chem. Res. 1982, 15, 178. (b)
Miyaura, N.; Suzuki, A. Chem. ReV. 1995, 95, 2457. (c) Suzuki, A. J.
Organomet. Chem. 1998, 576, 147.
Scheme 1
(3) (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.
(4) Ueda, M.; Saito, A.; Miyaura, N. Synlett 2000, 1637.
(5) (a) Sakai, M.; Hayashi, H.; Miyaura, N. Organometallics 1997, 16,
4229. For a review, see: (b) Fagnou, K.; Lautens, M. Chem. ReV. 2003,
103, 169.
10.1021/ol051501y CCC: $30.25
© 2005 American Chemical Society
Published on Web 08/18/2005

Table 1. Effect of Pd Source and Phosphine on the
Palladium-Catalyzed Reaction of Phenylboronic Acid to
4-Cyanobenzaldehyde
Table 2. Additive Effect of Chloroform on the
Palladium-Catalyzed Reaction of Phenylboronic Acid to
4-Cyanobenzaldehyde
entry
Pd source
ligand [mol %]
yield [%]b
entry
Pd source
ligand [mol %]
yield [%]b
1
2
3
4
5
6
7
8
Pd2(dba)3‚CHCl3
Pd2(dba)3‚CHCl3
Pd2(dba)3‚CHCl3
Pd2(dba)3‚CHCl3
Pd2(dba)3‚CHCl3
Pd2(dba)3‚CHCl3
Pd2(dba)3‚CHCl3
Pd2(dba)3‚CHCl3
Pd2(dba)3‚CHCl3
Pd2(dba)3
Pd(dba)2
[PdCl(π-C3H5)]2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
PPh3 (5)
PPh3 (10)
PPh3 (11)
PPh3 (15)
dppe (5)
dppp (5)
dppb (5)
dppf (5)
(R)-binap (5)
PPh3 (5)
PPh3 (5)
PPh3 (5)
PPh3 (5)
PPh3 (10)
PPh3 (15)
PPh3 (10)
PPh3 (5)
PPh3 (5)
none
95 (94)c
84
43
1
2
3
4
5
6
7
Pd2(dba)3‚CHCl3
Pd2(dba)3
Pd(dba)2
[PdCl(π-C3H5)]2
Pd(OAc)2
Pd(acac)2
PPh3 (2.5)
PPh3 (5)
PPh3 (5)
PPh3 (5)
PPh3 (10)
PPh3 (10)
PPh3 (5)
86
95
97
92
98
82
92
2
0 (0)d
0 (42)d
52
75
89e
0
0
0
0
0
0
0
PdCl2(CH3CN)2
a The reaction was carried out with 4-cyanobenzaldehyde (1.0 mmol),
phenylboronic acid (2.0 mmol), Cs2CO3 (1.0 mmol), Pd source (5 mol %),
and chloroform (0.01 mL) in 2.0 mL of toluene at 60 °C for 24 h.
9
10
11
12
13
14
15
16
17f
18
19
b Determined by H NMR spectroscopy using internal standard method.
1
(Table 2, entry 1). It was not effective though CH2Cl2 and
CCl4 had been used instead of CHCl3.
Results of the reaction of aldehydes with aryl boronic acids
are summarized in Table 3. Electronic effects both in the
Pd(acac)2
Pd(acac)2
PdCl2(CH3CN)2
Pd(PPh3)4
0
0
0
a
Table 3. 1,2-Addition of Arylboronic Acids to Aldehydes
The reaction was carried out with 4-cyanobenzaldehyde (1.0 mmol),
phenylboronic acid (2.0 equiv), Cs2CO3 (1.0 equiv), and Pd source (5 mol
%) in 2.0 mL of toluene at 60°C for 24 h. b Yields were relative to an
internal standard by 1H NMR spectroscopy. c Yield of product isolated by
silica gel column chromatography, based on 4-cyanobenzaldehyde. d The
reactions were carried out at 80 °C. e Corresponding alcohol was racemate.
f Cu(BF4)2‚6H2O (20 mol %) was added.
entry
ArB(OH)2
aldehyde
yield (%)b
1
2
3
4
5
6
7
8
PhB(OH)2
4-CF3C6H4CHO
4-MeOCOC6H4CHO
4-FC6H4CHO
99
88
84
73
70
58
70
56
75
86
87
84
52
<1
<1
71
75
PhB(OH)2
PhB(OH)2
PhB(OH)2
PhB(OH)2
PhB(OH)2
PhB(OH)2
PhB(OH)2
PhB(OH)2
PhCHO
2-naphthaldehyde
4-MeC6H4CHO
2-MeC6H4CHO
4-MeOC6H4CHO
2-MeOC6H4CHO
yields of the 1,2-addition products decreased with the
increase of the amount of triphenylphosphine (Table 1,
entries 1-4). Bidentate phosphines with small bite angles
such as dppe, dppp, and dppb showed lower performance
as a ligand (Table 1, entries 5-7). However, bidentate
phosphines with large bite angles were effective for the 1,2-
addition reaction (Table 1, entries 8 and 9). Noteworthy is
that no other palladium(II) complexes nor palladium(0)
complex precursors favor the 1,2-addition reaction (Table
1, entries 10-19).
9
10
11
12
13
14
15
16
17
4-MeOC6H4B(OH)2 2-naphthaldehyde
2-MeOC6H4B(OH)2 2-naphthaldehyde
4-MeC6H4B(OH)2
4-FC6H4B(OH)2
2-FC6H4B(OH)2
4-NCC6H4B(OH)2
4-FC6H4B(OH)2
2-FC6H4B(OH)2
2-naphthaldehyde
2-naphthaldehyde
2-naphthaldehyde
2-naphthaldehyde
4-NCC6H4CHO
4-NCC6H4CHO
From the results in Table 1, we reasoned that chloroform
was important. Thus, we tested the additive effect of
chloroform on the palladium-catalyzed addition (Table 2).
In the presence of a catalytic amount of chloroform, various
palladium complexes showed a similar effect as Pd2(dba)3‚
CHCl3 (Table 2, entries 2-7). The reaction proceeded
smoothly, although half the amount of PPh3 was used for
Pd when Pd2(dba)3‚CHCl3 was used as palladium source
a The reaction was carried out with aldehyde (1.0 mmol), arylboronic
acid (2.0 mmol), Cs2CO3 (1.0 mmol), Pd2(dba)3‚CHCl3 (0.025 mmol), and
PPh3 (0.05 mmol) in 2.0 mL of toluene at 80 °C for 24 h. b Yield of product
isolated by silica gel column chromatography, based on aldehyde.
aldehydes and in the arylboronic acids showed a remarkable
influence on the reaction; electron-withdrawing aldehydes
and arylboronic acids with a donating group reacted easily
(Table 3, entries 1-3, 10-12). On the other hand, electron-
rich aldehydes gave biarylmethanols in lower yields (Table
3, entries 6 and 8), although addition to ortho-substituted
electron-rich aldehydes such as 2-anisaldehyde and 2-
tolaldehyde proceeded smoothly (Table 3, entries 7 and 9).
Electron-deficient arylboronic acids reacted slowly with
electron-neutral aromatic aldehydes such as 2-naphthalde-
hyde (Table 3, entries 13-15), but the reaction was facilitated
with electron-withdrawing aldehydes such as 4-cyanoben-
zaldehyde (Table 3, entries 16 and 17).
(6) Cho, C. S.; Motofusa, S.; Ohe, K.; Uemura, S. J. Org. Chem. 1995,
60, 883.
(7) (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.
(8) Gibson, S.; Foster, D. F.; Eastham, G. R.; Tooze, R. P.; Cole-
Hamilton, D. J. Chem. Commun. 2001, 779.
(9) General Procedure. Pd complex (0.025 or 0.05 mmol, 5 mol %)
and phosphine (0.05 mmol, 5 mol %), arylboronic acid (2.0 mmol), aldehyde
(1.0 mmol), and Cs2CO3 (1.0 mmol) were dissolved in toluene (2 mL) and
chloroform (0.01 mL). After the mixture was stirred at 80 °C for 24 h,
then the product was extracted with CH2Cl2. The analytically pure alcohol
was obtained by chromatography on silica gel.
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Org. Lett., Vol. 7, No. 19, 2005

We propose the possible catalytic cycle of this reaction.
At first, phosphine and dichloromethyl-coordinating palla-
dium(II) intermediate 5 is generated by oxidative addition
of chloroform to phosphine-coordinated palladium(0) com-
plex 4, and dichloromethylpalladium(II) intermediate 5
produces a hydroxyl palladium(II) species 6 by counteranion
exchange (Scheme 2). Then, transmetalation between aryl-
Scheme 3
Scheme 2. Possible Intermediates
boronic acid and the hydroxyl palladium(II) species 6 occurs
to generate an arylpalladium(II) intermediate, and the inser-
tion of the aldehyde into the carbon-palladium bond affords
the palladium alkoxide. The palladium alkoxide complex is
hydrolyzed to give the corresponding alcohol, and the
hydroxyl palladium(II) species 6 is reproduced. Herrmann
et al. reported chloro(dichloromethyl)-palladium(II) coordi-
nated with two triphenylphosphines 7 that was prepared from
Pd(PPh3)4 with CHCl3.10 We used the complex 7 as a catalyst
for the addition of phenylboronic acid to 4-cyanobenzalde-
hyde at 60 °C (Scheme 3). As a result, the palladium complex
7 was similarly effective for the combination of Pd2(dba)3‚
CHCl3 with 2 equiv of PPh3 (Table 1, entry 2). There are
still some possibilities for catalytic intermediates, because
multinuclear palladium complexes were formed by the
reaction of Pd2(dba)3, polyhalomethane, and phosphine.11 We
tried other polyhalomethanes as an additive. Bromoform
(CHBr3), bromodichloromethane (CHBrCl2), and tetrachlo-
romethane (CCl4) proved much less effective for this reaction
(11%, 14%, 7% yields, respectively). Further mechanistic
study and application of this catalytic system are now
underway.
In conclusion, arylboronic acids react with aldehydes in
the presence of base and a catalytic amount of a palladium-
(0) complex with chloroform, affording the corresponding
secondary alcohols in good yield. General palladium com-
plexes have no catalytic activity without chloroform but
become active by addition of a catalytic amount of chloro-
form to the reaction mixture.
Acknowledgment. This work was partially supported by
Doshisha University’s Research Promotion Fund and a grant
to RCAST at Doshisha University from the Ministry of
Education, Japan.
Supporting Information Available: Spectra and detailed
descriptions of experimental procedures. This material is
available free of charge via the Internet at http://pubs.acs.org.
(10) Herrmann, W. A.; Thiel, W. R.; Brossmer, C.; O¨ fele, K.; Priermeier,
T.; Scherer, W. J. Organomet. Chem. 1993, 461, 51.
(11) Mingos, D. M. P.; Vilar, R. J. Organomet. Chem. 1998, 557, 131.
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