Palladium(II)-catalyzed addition of arylboronic acid to nitriles

Article abstract of DOI:10.1016/j.tetlet.2006.07.074

The addition of arylboronic acid to nitriles catalyzed by palladium(II) species in the presence of bipyridine as the ligand was developed. The use of bipyridine is crucial for changing the properties of arylpalladium species from more electrophilic to more nucleophilic making the reaction possible.

Full text of DOI:10.1016/j.tetlet.2006.07.074

Tetrahedron Letters 47 (2006) 6765–6768
Palladium(II)-catalyzed addition of arylboronic acid to nitriles
Baowei Zhao and Xiyan Lu*
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry,
Chinese Academy of Sciences, 354 Fenglin Lu, Shanghai 200032, China
Received 25 June 2006; revised 14 July 2006; accepted 17 July 2006
Available online 7 August 2006
Abstract—The addition of arylboronic acid to nitriles catalyzed by palladium(II) species in the presence of bipyridine as the ligand
was developed. The use of bipyridine is crucial for changing the properties of arylpalladium species from more electrophilic to more
nucleophilic making the reaction possible.
Ó 2006 Elsevier Ltd. All rights reserved.
Insertion of carbon–carbon multiple bonds into carbon–
transition-metal bonds, as a facile method of carbon–
carbon bond formation, is a very important elementary
reaction in organotransition-metal chemistry.1 How-
ever, in contrast to the tremendous amount of reports
about the insertion of carbon–carbon multiple bonds
into carbon–transition-metal bonds, direct insertion of
carbon–heteroatom multiple bonds, such as carbonyl,
imino, and cyano groups, without using stoichiometric
organometallic reagents received scant attentions.1 In
general, the organometallic compounds of late transi-
tion metals are less nucleophilic than other organomet-
allics. While the arylpalladium species are commonly
used as electrophiles in the carbon–carbon coupling
reactions and in the reaction with alcohols and amines,1
only few reports of the use of the arylpalladium species
as nucleophiles to react with the polar electrophilic mul-
tiple bonds were reported.2
for the effect of DMSO involves the facile coordination
between DMSO and Pd, which may either stabilize any
Pd(II) reaction intermediate or facilitate the reoxidation
of Pd(0) to Pd(II) (presumably by air) should the Pd(II)
ever be reduced to Pd(0).3f
Our group has recently reported the Pd(II)-catalyzed
intramolecular addition of vinylpalladium species to
the carbonyl and cyano groups in the presence of
bipyridine (bpy) as the ligand.4 In this reaction, the
vinylpalladium intermediate was formed from the acet-
oxypalladation of the alkyne. The formed vinylpalla-
dium species will be relatively nucleophilic due to the
presence of the acetoxy group in the olefinic bond,
making the addition of vinylpalladium species to the
carbonyl and nitrile group possible (Scheme 1).4
In our study of the Pd(II)-catalyzed conjugate addition
of phenylboronic acid to a,b-unsaturated carbonyl com-
pounds,5 trace amount of aceotophenone or benzophe-
none was obtained when acetonitrile or phenylnitrile
was used as the solvent (Scheme 2). It was suggested that
these carbonyl compounds were formed from the addi-
tion of phenylboronic acids to nitrile compounds.
In general, nitriles are stable to organopalladium spe-
cies. Thus, acetonitrile can be used as the solvent in
the palladium-catalyzed reactions. PdCl2(RCN)2 (R =
Me, Ph) are widely used as Pd catalysts. Recently, Lar-
ock’s group reported a series of papers dealing with the
addition of arylpalladium species to the cyano group
using Pd(0) to initiate the reaction in the presence of
DMF.3a–e They also used the Pd(II) species as the cata-
lyst in the presence of DMSO.3f Larock’s explanation
R
R
R
N
C
NPd(II)
Pd
X
NHCOMe
AcO
O
AcO
X
X
Keywords: Palladium; Nitrile; Bipyridine; Nucleophilic addition;
X = CE2, O, NTs
Ligand.
*
Scheme 1. The addition of 2-acetoxyvinylpalladium species to the
Corresponding author. Tel.: +86 21 54925158; fax: +86 21
nitrile group.
64166128; e-mail: xylu@mail.sioc.ac.cn
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.07.074

6766
B. Zhao, X. Lu / Tetrahedron Letters 47 (2006) 6765–6768
The best result was obtained when 2,20-bipyridine (bpy)
O
O
/bpy
Pd(OAc)2
THF/H2O
Ph
O
+
+
was used as the ligand (Table 2, entry 2). In the absence
of bpy, the reaction mixture became black immediately
and only a small amount of the coupling product diphe-
nyl was obtained (Table 2, entry 1). 2,20-Bipyridines
with electron-donating (OMe) or electron-withdrawing
(NO2) groups at 4,40-positions gave lower yields than
the nonsubstituted bipyridines (Table 2, entries 3 and 4).
Phenanthroline gave a medium yield (Table 2, entry 5).
Other ligands did not give good results. These results
may imply that the ligand 2,20-bipyridine plays an
important role and is crucial for this reaction. It may
stabilize the divalent palladium species and inhibit the
coupling reaction of two phenylboronic acids to form
the diphenyl.5,7 The success of the addition reaction of
phenylboronic acid to nitriles may also imply that the
presence of bpy makes the arylpalladium species from
electrophilic to more nucleophilic.
PhB(OH)2
Ph
Ph
Ph
Ph
+
CH3CN (or PhCN)
Ph
O
O
or
Ph
Ph
trace
Scheme 2. Reaction of phenylboronic acid and a,b-unsaturated
carbonyl compounds under Pd(II) catalysis.
With this inspiring result in hand, we optimized the reac-
tion conditions. Phenylacetonitrile was chosen as the
substrate. The results are shown in Table 1.
When we used the condition reported in conjugated
addition,5 the addition product was obtained in 57%
yield (Table 1, entry 1). The addition of bases such as
alkoxy, hydroxy, and fluoride anions exerts a remark-
able accelerating effect on the transmetalation step of
phenylboronic acid and the palladium acetate.6 The
yield increased to 71% (Table 1, entry 2) when 1 equiv
of KFÆ2H2O (based on PhB(OH)2) was added in the
reaction. The best yield (85%) was obtained in the pres-
ence of 2 equiv of KFÆ2H2O at 80 °C (Table 1, entry 3).
In the absence of HOAc, the results are not good (Table
1, entries 9–11). A similar result could be obtained if
replacing THF by 1,4-dioxane (Table 1, entry 12). The
following condition was chosen as the optimized condi-
tion. PhB(OH)2 (1.5 mmol), RCN (0.5 mmol), Pd(OAc)2
(0.025 mmol), bpy (0.1 mmol), and KFÆ2H2O (3 mmol)
in the presence of HOAc (0.5 ml), THF (0.25 ml), and
H2O (0.15 ml) at 80 °C.
The ratio of Pd(OAc)2 to bpy was surveyed too (Table 3).
The yields of ketone were decreased with the decrease of
the amount of bpy. Too much of bpy made the rate of
the reaction slower and decreased the yield.
Other phenylboron compounds were used for this
reaction and arylboronic acid showed the best result
(Table 4).
With the optimized condition in hand, the addition of
arylboronic acids to different kinds of nitriles studied.
The results are shown in Table 5.
From the table, it was shown that substituted benzophe-
nones were obtained in from 31% to 70% yield. The aryl
palladium species could also add to the alkylnitriles, but
the yields were lower (Table 5, entries 10–13). It should
be noted that the 4-nitrophenylnitrile gave higher yield
Different ligands were surveyed in the reaction. The
results are summarized in Table 2.
Table 1. Palladium(II)–bipyridine catalyzed addition of phenylboronic acid to phenylacetonitrilea
O
Pd(OAc)2
B(OH)2
Ph
bpy
+
PhCH2CN
additive
solvent
2days
3 eq
Entry
Solvent
Additiveb KFÆ2H2O (equiv)
T (°C)
Yieldc (%)
1
2
3
4
5
6
7
8
HOAc/THF/H2O (0.5 ml/0.25 ml/0.15 ml)
HOAc/THF/H2O (0.5 ml/0.25 ml/0.15 ml)
HOAc/THF/H2O (0.5 ml/0.25 ml/0.15 ml)
HOAc/THF/H2O (0.5 ml/0.25 ml/0.15 ml)
HOAc/THF/H2O (0.5 ml/0.25 ml/0.15 ml)
HOAc/THF/H2O (0.5 ml/0.25 ml/0.15 ml)
HOAc/THF/H2O (0.5 ml/0.25 ml/0.15 ml)
HOAc/THF (0.5 ml/0.25 ml)
THF/H2O (0.25 ml/0.15 ml)
THF (1.0 ml)
THF (1.0 ml)
HOAc/dioxane/H2O (0.5 ml/0.25 ml/0.15 ml)
HOAc/THF/H2O (0.1 ml/1.0 ml/0.15 ml)
0
1
2
3
2
2
2
2
2
0
2
2
2
80
80
80
80
40
60
100
80
80
80
80
80
80
57
71
85
85
7
44
63
80
58
69
Trace
83
49
9
10
11
12
13
a Reaction conditions: PhB(OH)2 (1.5 mmol), PhCH2CN (0.5 mmol), Pd(OAc)2 (0.025 mmol), bpy (0.10 mmol) in solvents at the indicated
temperature.
b The amount of KFÆ2H2O in equivalents based on that of PhB(OH)2.
c Isolated yield.

B. Zhao, X. Lu / Tetrahedron Letters 47 (2006) 6765–6768
6767
Table 2. The ligand effect of the addition of phenylboronic acid to
phenylacetonitrile catalyzed by Pd(II) speciesa
Table 4. The addition of phenylboron compounds to phenylacetonit-
rilea
Entry
1
Ligand
none
Yieldb (%)
Pd black
O
Pd(OAc)2
bpy
Ph
PhCH2CN
PhM
+
2
85
Entry
PhM (equiv based on PhCH2CN)
Yieldb (%)
N
N
1
2
3
4
PhB(OH)2 (3)
NaBPh4 (1)
(PhBO)3 (1)
PhBF3K (3)
85
Trace
72
OMe
OMe
3
68
63
N
N
a Reaction conditions: phenylboron compounds, PhCH2CN (0.5
mmol), Pd(OAc)2 (0.025 mmol), bpy (0.1 mmol), and KFÆ2H2O
(2 equiv based on the phenylboron compounds) in HOAc (0.5 ml),
THF (0.25 ml), and H2O (0.15 ml) at 80 °C for 2 days.
b Isolated yield.
NO2
NO2
4
5
46
56
N
N
N
N
N
Table 5. The addition of arylboronic acids to nitrilesa
6
7
4
6
Pd(OAc)2
CO2Et
bpy
O
+
ArB(OH)2
RCN
additive
solvent
2days
Ar
R
N
N
N
Entry Ar–
R–
Bn
PhOCH2
Ph
4-MeO–C6H4
4-NO2–C6H4
3-NO2–C6H4
2-NH2–C6H4
2,6-Di-F–C6H3
2-Py
Product Yieldb (%)
8
Trace
1
2
3
4
5c
6
7
8
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
1
2
85
84
67
60
70
63
31
31
52
15
31
38
13
65
67
80
58
3
4
9
Trace
5
OH
O
N
O
6
7
8
9
9
10
No reaction
10
11
12
13
14
15
16
17
C2H5
10
11
12
13
14
15
16
17
nC3H7
a Reaction conditions: PhB(OH)2 (1.5 mmol), PhCH2CN (0.5 mmol),
Pd(OAc)2 (0.025 mmol), ligand (0.10 mmol), KFÆ2H2O (3 mmol) in
HOAc (0.5 ml), THF (0.25 ml), and H2O (0.15 ml) at 80 °C for
2 days.
nC5H11
Cl(CH2)3
4-Me–C6H4 Bn
b-Naphthyl
4-Cl–C6H4
4-F–C6H4
Bn
Bn
Bn
b Isolated yield.
a Reaction conditions:8 ArB(OH)2 (1.5 mmol), RCN (0.5 mmol),
Pd(OAc)2 (0.025 mmol), bpy (0.1 mmol), KFÆ2H2O (3 mmol) in
HOAc (0.5 ml), THF (0.25 ml), and H2O (0.15 ml) at 80 °C for
2 days.
than other arylnitriles (Table 5, entry 5). It should be
noted here that the nitro group could tolerate the reac-
tion conditions, while they are reactive in the presence
of Grignard reagents or lithium reagents. 2-Aminophen-
ylnitrile which has active hydrogens can still react nor-
mally although the yield is not satisfactory (Table 5,
entry 7).
b Isolated yield.
c The reaction was conducted for 7 days, but the yield did not change
much (73%).
The possible mechanism for this palladium(II) catalyzed
addition reaction of arylboronic acids and nitriles is
proposed as Scheme 3.
Table 3. The effect of Pd(OAc)2/bpy on the reactiona
Entry
Pd(OAc)2/bpy
Yieldb
1
2
3
4
1/1
1/2
1/4
1/6
70
75
85
67
First, transmetalation of arylboronic acids and palla-
dium acetate generated arylpalladium species A, which
was followed by the coordination of nitrile giving inter-
mediate B. The ligand bpy made the arylpalladium spe-
cies more nucleophilic resulting in the addition of the
arylpalladium species to the C„N bond to form inter-
mediate C. The protonolysis of C gave D and regener-
a Reaction conditions: PhB(OH)2 (1.5 mmol), PhCH2CN (0.5 mmol),
Pd(OAc)2 (0.025 mmol), KFÆ2H2O (3 mmol) and bpy in HOAc
(0.5 ml), THF (0.25 ml), and H2O (0.15 ml) at 80 °C for 2 days.
b Isolated yield.

6768
B. Zhao, X. Lu / Tetrahedron Letters 47 (2006) 6765–6768
Pd(OAc)2/bpy
References and notes
O
Ar
hydrolysis
R
ArB(OH)2
1. For reviews: (a) Tsuji, J. Transition Metal Reagents and
Catalysits; Wiley: Chichester, 2004; (b) Diederich, F.;
Stang, P. J. Metal-Catalyzed Cross-Coupling Reactions;
Wiley-VCH: Weinheim, 1998; (c) de Meijere, A.; Diederich,
F. Metal-Catalyzed Cross-Coupling Reactions, 2nd ed.;
John Wiley & Sons: Weinheim, Germany, 2004.
(bpy)Pd(OAc)2
NH
Ar
R
D
ArPd(OAc)(bpy)
A
2. (a) Tamaru, Y. In Handbook of Organopalladium Chemistry
for Organic Synthesis; Negishi, E.-i., Ed.; Wiley: New York,
2002; Vol. 2, pp 1917–1943, and references cited therein; (b)
Miura, M.; Nomura, M. Top. Curr. Chem. 2002, 219, 211;
(c) Hassen, J.; Sevignon, M.; Gozzi, C.; Schulz, E.;
Lemaire, M. Chem. Rev. 2002, 102, 1359; (d) Culkin, D.
A.; Hartiwig, J. F. Acc. Chem. Res. 2003, 36, 234; (e)
Ueura, K.; Satoh, T.; Miura, M. Org. Lett. 2005, 7, 2229;
protonlysis
RCN
OAc
N
(bpy)Pd
Ar
(bpy)Pd
Ar
N
C
R
R
B
addition
(f) Kamijo, S.; Sasaki, Y.; Kanazawa, C.; Schusseler, T.;
¨
Yamamoto, Y. Angew. Chem., Int. Ed. 2005, 44, 7718.
3. (a) Larock, R. C.; Tian, Q.; Pletnv, A. A. J. J. Am. Chem.
Soc. 1999, 121, 3238; (b) Pletnv, A. A.; Larock, R. C.
Tetrahedron Lett. 2002, 43, 2133; (c) Pletnv, A. A.; Tian, Q.;
Larock, R. C. J. Org. Chem. 2002, 67, 9276; (d) Pletnv, A.
A.; Tian, Q.; Larock, R. C. J. Org. Chem. 2002, 67, 9428;
(e) Tian, Q.; Pletnv, A. A.; Larock, R. C. J. Org. Chem.
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Chem. 2006, 71, 3551.
4. Zhao, L.; Lu, X. Angew. Chem., Int. Ed. 2002, 41, 4343.
5. Lu, X.; Lin, S. J. Org. Chem. 2005, 70, 9651.
6. (a) Suzuki, A. Organoboranes in Organic Synthesis; Hok-
kaido University: Sapporo, Japan, 2004; (b) Miyaura, N.;
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S.; Watanabe, Y. Organometallics 2002, 21, 1674.
Scheme 3. Possible mechanism for the Pd(II)-catalyzed addition of
arylboronic acids to nitriles.
ated the palladium catalyst. Hydrolysis of D yielded the
arylketones as the products.
In summary, we developed a Pd(II)-catalyzed addition
of arylboronic acids to C„N bond in the presence of
2,20-bipyridine as a ligand to yield arylketones with
moderate to excellent yield. The use of 2,20-bipyridine,
which may switch the arylpalladium species from more
electrophilic to more nucleophilic, was crucial in this
reaction. Further study about the role of 2,20-bipyri-
dines is underway in our laboratory.
7. (a) Zhao, L.; Lu, X.; Xu, W. J. Org. Chem. 2005, 70, 4069;
(b) Zhao, L.; Lu, X. Org. Lett. 2002, 4, 3903.
8. Typical procedure for the addition of arylboronic acid to
nitriles: To a Schlenk tube were added phenylboronic acid
(183 mg, 1.5 mmol), phenylacetonitrile (58.5 mg, 0.5 mmol),
KFÆ2H2O (282 mg, 3.0 mmol), Pd(OAc)2 (5.6 mg, 0.025
mol), bpy (15.6 mg, 0.10 mmol), HOAc (0.5 ml), THF
(0.25 ml), and H2O (0.15 ml) under argon. The mixture
was stirred and heated at 80 °C for 2 days until the substrate
disappeared as monitored by TLC. The reaction mixture
was neutralized with saturated NaHCO3 solution and then
extracted with Et2O. The combined ether solution was
washed with brine, dried by MgSO4, and concentrated. The
residue was purified by flash chromatography (EtOAc/
petroleum ether = 1/50) to give product 1 with 85% yield as
a white solid. The detailed characterization data of the
products were included in Supplementary data.
Acknowledgements
We thank the National Natural Sciences Foundation of
China and Chinese Academy of Sciences for the finan-
cial Support.
Supplementary data
Experimental procedure and characterization data for
compounds 1–17 are provided. Supplementary data
associated with this article can be found, in the online
version, at doi:10.1016/j.tetlet.2006.07.074.