Cationic palladium(II)-catalyzed addition of arylboronic acids to nitriles. One-step synthesis of benzofurans from phenoxyacetonitriles

Article abstract of DOI:10.1021/ol062438v

(Chemical Equation Presented) A cationic palladium complex catalyzed addition of arylboronic acids to nitrites to yield aryl ketones with moderate to good yields was developed. A one-step synthesis of benzofurans from phenoxyacetonitriles under the catalysis of [(bpy)Pd⁺(μ-OH)] ₂(^-OTf)₂ or [(bpy)Pd²⁺(H ₂O₂)₂](^-OTf)₂ was developed which showed that the cationic palladium catalyst is highly active for these addition reactions.

Full text of DOI:10.1021/ol062438v

ORGANIC
LETTERS
2006
Vol. 8, No. 26
5987-5990
Cationic Palladium(II)-Catalyzed Addition
of Arylboronic Acids to Nitriles.
One-Step Synthesis of Benzofurans
from Phenoxyacetonitriles
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
xylu@mail.sioc.ac.cn
Received October 4, 2006
ABSTRACT
A cationic palladium complex catalyzed addition of arylboronic acids to nitriles to yield aryl ketones with moderate to good yields was
-
+
-
developed. A one-step synthesis of benzofurans from phenoxyacetonitriles under the catalysis of [(bpy)Pd+(µ-OH)]2( OTf)2 or [(bpy)Pd2 (H2O)2]( OTf)2
was developed which showed that the cationic palladium catalyst is highly active for these addition reactions.
Addition of carbon-metal species to carbon-heteroatom
multiple bonds, such as the carbonyl, imino, and nitrile
groups, is an important reaction of carbon-carbon bond
formation. However, in contrast to the many reports using
stoichiometric amounts of organometallic reagents, catalytic
reactions using transition-metal catalysts received scant
attention.1 In general, the organometallic compounds of late
transition metals are less nucleophilic than other organome-
tallics. Although the arylpalladium species are usually used
as electrophiles in carbon-carbon coupling reactions and
reaction with alcohols and amines,1,2 only few reports on
the use of the arylpalladium species as nucleophiles to react
with the polar electrophilic multiple bonds exist.2
In general, nitriles are stable to organopalladium species.
Thus, acetonitrile or benzonitrile can be used as the solvent
in the palladium-catalyzed reactions. PdCl2(RCN)2 (R ) Me,
Ph) is widely used as Pd catalysts. Recently, Larock’s group
reported a series of papers dealing with the addition of
arylpalladium species to the nitrile group using Pd(0)-
catalyzed reactions in the presence of DMF.3a-e They also
used the Pd(II) species as the catalyst in the presence of
DMSO to study the addition of arenes to nitriles.3f,g In the
same paper, the first example of the addition of arylboronic
acids to nitriles was reported. Vicente has also reported the
(1) For reviews, see: (a) Tsuji, J. Transition Metal Reagents and
Catalysts; 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.
(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 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) Tsuji, J. Palladium in Organic
Synthesis; Springer: New York, 2005; p 211 and references therein. (f)
Ueura, K.; Satoh, T.; Miura, M. Org. Lett. 2005, 7, 2229. (g) Kamijo, S.;
Sasaki, Y.; Kanazawa, C.; Schu¨sseler, T.; Yamamoto, Y. Angew. Chem.,
Int. Ed. 2005, 44, 7718.
(3) (a) Larock, R. C.; Tian, Q.; Pletnev, A. A. J. Am. Chem. Soc. 1999,
121, 3238. (b) Pletnev, A. A.; Larock, R. C. Tetrahedron Lett. 2002, 43,
2133. (c) Pletnev, A. A.; Tian, Q.; Larock, R. C. J. Org. Chem. 2002, 67,
9276. (d) Pletnev, A. A.; Tian, Q.; Larock, R. C. J. Org. Chem. 2002, 67,
9428. (e) Tian, Q.; Pletnev, A. A.; Larock, R. C. J. Org. Chem. 2003, 68,
339. (f) Zhou, C.; Larock, R. C. J. Am. Chem. Soc. 2004, 126, 2302. (g)
Zhou, C.; Larock, R. C. J. Org. Chem. 2006, 71, 3551. (h) Yang, C.-C.;
Sun, P.-J.; Fang, J.-M. J. Chem. Soc., Chem. Commun. 1994, 2629. (i) Yang,
C.-C.; Tai, H.-M.; Sun, P.-J. Synlett 1997, 812. (j) Yang, C.-C.; Tai, H.-
M.; Sun, P.-J. J. Chem. Soc. Perkin Trans. 1 1997, 2843. (k) Vicente, J.;
Abad, J. A.; Lo´pez-Sa´ez, M.-J.; Jones, P. G. Angew. Chem., Int. Ed. 2005,
44, 6001.
10.1021/ol062438v CCC: $33.50
© 2006 American Chemical Society
Published on Web 11/24/2006

insertion of nitriles into a C-Pd bond assisted by the ortho-
hydroxy group.3k
Table 1. Optimization of Reaction Conditions for the Addition
of PhB(OH)2 to Phenylacetonitrilea
Our group has reported the Pd(II)-catalyzed intramolecular
addition of vinylpalladium species to the nitrile groups in
the presence of 2,2′-bipyridine (bpy) as the ligand.4 Recently,
we also reported the Pd(OAc)2-catalyzed addition of aryl-
boronic acids to nitriles in the presence of bpy.5 In both
reactions, bpy is crucial for the reactions implying that the
presence of bpy can stabilize the arylpalladium species and
increase its reactivity.
Compared to the neutral palladium species, the cationic
palladium species has vacant coordination sites and shows
a harder metal property.6,7 It occurred to us that the cationic
palladium complexes might also catalyze the addition of
arylboronic acids to nitriles due to their high Lewis acid
property. We report herein the cationic palladium complex
catalyzed addition of arylboronic acids to nitriles and the
one-step synthesis of benzofuran derivatives.
First, (dppp)Pd2+(H2O)2(-OTf)2 (catalyst A)8 was used as
the catalyst in this reaction. Unfortunately, the reaction
mixtures became dark quickly in THF or in CH3NO2 with
low yields of products (Table 1, entries 1 and 2). In our
previous work, we reported that the ligand bpy is crucial
for the reaction.4 The cationic palladium complexes contain-
ing bpy as the ligand, [(bpy)Pd+(µ-OH)]2(-OTf)2 (catalyst
B) and [(bpy)Pd2+(H2O)2](-OTf)2 (catalyst C), were chosen
as the catalysts.9,10a To our delight, the catalysts were
effective and the reaction could take place without any
protection from air and moisture. After screening the solvent,
we found that the best result could be obtained in CH3NO2
(Table 1, entry 9). It is worth noting that water could be
used as the solvent for this reaction (Table 1, entry 8).
entry
Pd catalyst
solvent
yieldc (%)
1
2
3
Ab
Ab
B
THF
21
19
67
CH3NO2
HOAc/THF/H2O
(0.5:0.25:0.15, v/v/v)
HOAc
4
5
6
7
8
9d
10
B
B
B
B
B
B
B
23
78
43
51
85
94
73
THF
dioxane
iPrOH
H2O
CH3NO2
CH3NO2/dioxane
(8:1, v/v)
DMF
11
12
B
B
36
26
DMSO
a Reaction conditions: PhB(OH)2 (1.5 mmol), phenylacetonitrile (0.5
mmol), [(bpy)Pd+(µ-OH)]2(-OTf)2 (catalyst B, 3.5 mol %) in solvent (2
mL) at 80 °C for 2 days. b 5 mol %. c Isolated yield. d 30 h.
With the optimized conditions in hand, the scope of the
reaction was studied as shown in Table 3. The yields in most
cases are higher than that using Pd(OAc)2 as the catalyst as
we reported recently.5 Arylboronic acids with electron-
donating groups gave better yields than those with electron-
withdrawing groups (Table 3, entries 2, 3, and 6). It is worth
noting that those groups, which are reactive in the presence
of Grignard reagents or lithium reagents such as the nitro,
hydroxyl, and acetate groups (AcO-), could tolerate the
reaction conditions (Table 3, entries 9-12). It is especially
attractive that the reaction behaves with high chemoselec-
tivity between nitrile groups and Br- or TfO- groups which
The influence of the amount of the phenylboronic acids
is shown in Table 2. A high yield was also obtained even
using 2 equiv of phenylboronic acid reacting at 80 °C (Table
2, entry 3). Under reflux conditions, the amount of phenyl-
boronic acid could be reduced to 1.5 equiv and the loading
of the catalyst could be reduced to 1 mol % with not much
change in the yield (Table 2, entry 6).
(4) Zhao, L.; Lu, X. Angew. Chem., Int. Ed. 2002, 41, 4343.
(5) Zhao, B.; Lu, X. Tetrahedron Lett. 2006, 47, 6765.
(6) For reactions catalyzed by cationic palladium species, see: (a)
Yamamoto, A. J. Organomet. Chem. 1995, 500, 337. (b) Coates, G. W.
Chem. ReV. 2000, 100, 1223. (c) Widenhoefer, R. A. Acc. Chem. Res. 2002,
35, 905. (d) Sodeoka, M.; Hamashima, Y. Bull. Chem. Soc. Jpn. 2005, 78,
941. (e) Mikami, K.; Hatano, M.; Akiyama, K. Top. Organomet. Chem.
2005, 14, 279 and references therein.
(7) For the reaction of arylboronic acids with a cationic palladium
catalyst, see: (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.
Table 2. [(bpy)Pd+(µ-OH)]2(-OTf)2-Catalyzed Addition of
PhB(OH)2 to Phenylacetonitrilea
PhB(OH)2
(equiv)
catalyst
(mol %)
t
time
(h)
yieldb
(%)
entry
(°C)
(8) Stang, P. J.; Cao, D. H.; Poulter, G. T.; Arif, A. M. Organometallics
1995, 14, 1110.
1
2
3
4
5
6
3.0
2.5
2.0
1.5
1.5
1.5
3.5
3.5
3.5
3.5
3.5
1.0
80
80
80
80
reflux
reflux
48
48
48
48
24
24
94
89
87
77
92
91
(9) Catalyst B is very stable to air and moisture. 1H NMR spectra showed
clearly the bridged OH in catalyst B at 3.34 and 2.79 ppm. Its structure
was confirmed by X-ray crystallography (see Supporting Information).10a
Catalyst C showed 1H NMR spectra identical with those of the reported
data.10b Catalyst B and catalyst C can be converted to each other under the
acidic or basic conditions according to the literature.10c
(10) Complex [(bpy)Pd+(µ-OH)]2(-OTf)2 has been reported in the
literature, but no X-ray crystallographic data were given. See: (a) Vicente,
J.; Abad, J.-A.; Gil-Rubio, J. Organometallics 1996, 15, 3509. (b) Aeby,
A.; Consiglio, G. Inorg. Chim. Acta 1999, 296, 45. (c) Wimmer, S.; Castan,
P.; Wimmer, F. L.; Johnson, N. P. Inorg. Chim. Acta 1988, 142, 13.
a Reaction conditions: PhB(OH)2, phenylacetonitrile (0.5 mmol),
[(bpy)Pd+(µ-OH)]2(-OTf)2 (catalyst B) in CH3NO2 (2 mL). b Isolated yield.
5988
Org. Lett., Vol. 8, No. 26, 2006

Table 3. [(bpy)Pd+(µ-OH)]2(-OTf)2-Catalyzed Addition of
Table 4. Synthesis of Benzofurans from the Addition of
Arylboronic Acids to Phenoxyacetonitriles under the Catalysis
of a Cationic Palladium Complex
Arylboronic Acids to Nitrilesa
entry
Ar
R
product
yield (%)d
1b
2
Ph
Bn
Bn
Bn
Bn
Bn
Bn
Ph
3a
3b
3c
3d
3e
3f
91
86
87
63
89
80
88
78
86
92
91
82
78
91
91
52
59
72
35
4-Me-C6H4
3
4-MeO-C6H4
4
R-naphthyl
5
â-naphthyl
6
4-F-C6H4
Ph
substrate
yield (%)c
7
3g
3h
3i
8
Ph
4-MeO-C6H4
4-NO2-C6H4
3-NO2-C6H4
4-HO-C6H4
4-AcO-C6H4
4-Br-C6H4
4-TfO-C6H4
PhOCH2
entry
1
4
Pd catalyst time (h)
5
6
9
Ph
10
11
12
13
14
15
16c
17c
18c
19c
Ph
3j
3k
3l
3m
3n
3o
3p
3q
3r
3s
1
2
3
4
5
6
1a
1b
1f
1g
1h
1a
4a
4a
4a
4a
4a
4b
Ba
Ba
Ba
Ba
Ba
Ba
Cb
Ba
Cb
Cb
Cb
Cb
Cb
Ba
Cb
Cb
Cb
Cb
Cb
48
48
48
48
48
9
12
21
11
10
18
20
23
14
24
22
12
18
24
5aa (62)
Ph
Ph
5ba (15) 6ba (56)
5fa (20) 6fa (80)
5ga (67)
5ha (52) 6ha (35)
5ab (82)
5ab (89)
5bb (58) 6bb (42)
5bb (89)
5cb (64)
5db (39) 6db (54)
5eb (79)
5fb (91)
5gb (65)
Ph
Ph
Ph
Ph
C2H5
Ph
n-C3H7
Ph
n-C5H11
Ph
Cl(CH2)3
7
1b
4b
a Reaction conditions: ArB(OH)2 (0.38 mmol), RCN (0.25 mmol),
[(bpy)Pd+(µ-OH)]2(-OTf)2 (catalyst B, 1 mol %) in CH3NO2 (1 mL) at
reflux for about 24 h. b See Table 2. c Reaction conditions: PhB(OH)2 (1.5
mmol), RCN (0.5 mmol), [(bpy)Pd+(µ-OH)]2(-OTf)2 (catalyst B, 3.5 mol
%) in CH3NO2 (2 mL) at 80 °C for 48 h. d Isolated yield.
8
9
1c
1d
1e
1f
1g
1h
1i
1j
1k
1l
4b
4b
4b
4b
4b
4b
4b
4b
4b
4b
10
11
12
13
14
15
16
17
are highly reactive to Pd(0) species11 (Table 3, entries 13
and 14). For other alkyl nitriles, good results could also be
obtained (Table 3, entries 15-19).
5hb (86)
5ib (69)
5jb (84)
5kb (70)
The possible mechanism for this [(bpy)Pd+(µ-OH)]2(--
OTf)2 (catalyst B) catalyzed addition reaction of arylboronic
acids and nitriles is proposed as Scheme 1.
5lb (61) 6lb (30)
a ArB(OH)2 (1.5 mmol), 4 (0.5 mmol), catalyst B (5 mol %) in CH3NO2
(2.0 mL) at 80 °C. b ArB(OH)2 (0.3 mmol), 4 (0.2 mmol), catalyst C (5
mol %) in CH3NO2 (1.0 mL) at reflux. c Isolated yield.
Scheme 1. Proposed Mechanism for the Addition of
Arylboronic Acids to Nitriles Catalyzed by Catalyst B
presence of the solvent or the substrate RCN.12 Because of
the high oxophilicity of boron, the coordination of the
hydroxyl group with boronic acid made the transmetalation
step (b) easily occurring to form the intermediate c.7b Because
of the vacant coordination site on the palladium, nitriles could
coordinate with it very easily to generate intermediate d and
were activated by cationic Pd species due to its higher Lewis
acidity. The cationic form made the arylpalladium species
more nucleophilic resulting in the smooth addition of the
arylpalladium species to the nitrile to form the intermediate
e. The protonolysis of e gave f and regenerated the palladium
catalyst. Hydrolysis of f yielded the aryl ketones as the
products.
The important results we found in the study of the
reactions of different nitriles encouraged us to study a new
area of the reaction. When 3,5-dimethoxyphenoxyacetonitrile
(4a) was used as the substrate, 4,6-dimethoxy-3-phenylben-
zofuran was isolated as the product in 62% yield in one step.
(11) Guy, M.; Alois, V.; Richard, B. Tetrahedron Lett. 1994, 35, 3277.
(12) (a) Hamashima, Y.; Hotta, D.; Sodeoka, M. J. Am. Chem. Soc. 2002,
124, 11240. (b) Kina, A.; Iwamura, H.; Hayashi, T. J. Am. Chem. Soc.
2006, 128, 3904.
First, the dimeric catalyst [(bpy)Pd+(µ-OH)]2(-OTf)2
(catalyst B) dissociated to the monomeric form a in the
Org. Lett., Vol. 8, No. 26, 2006
5989

Scheme 2. Possible Pathways of the Formation of Benzofurans from 3,5-Dimethoxy-phenoxyacetonitriles under the Catalysis of a
Cationic Palladium Complex
With this result in hand, we turned our attention to the
one-step synthesis of 3-substituted benzofurans from the
addition of arylboronic acids to phenoxyacetonitriles under
the catalysis of catalyst B or catalyst C. The results are
summarized in Table 4.
R-phenoxyacetophenones.14 The formation of benzofurans
may proceed via the following pathways (Scheme 2).
First, arylboronic acids were added to the nitrile group of
3,5-dimethoxy-2-phenoxyacetonitrile forming the aryl ke-
tones. The cationic palladium species acted as a Lewis acid
to activate the carbonyl group, and then Friedel-Crafts
reaction took place (as shown in g) to form the intermediate
h. Then, benzofuran derivatives were formed after dehydra-
tion of h. Of course, another pathway (2) through the
palladium(II)-catalyzed C-H activation of the activated
benzene ring forming g′ first and then nucleophilic attack to
the carbonyl group could not be excluded.
In summary, we have developed a cationic palladium
complex catalyzed addition of arylboronic acids to nitriles
to yield aryl ketones with moderate to good yields. The
structure of the catalyst [(bpy)Pd+(µ-OH)]2(-OTf)2 (catalyst
B) was confirmed by X-ray crystallography. A one-step
synthesis of benzofurans from phenoxyacetonitriles under
the catalysis of [(bpy)Pd+(µ-OH)]2(-OTf)2 or [(bpy)Pd2+-
(H2O)2](-OTf)2 was developed. The results showed that the
cationic palladium catalyst is highly active for these addition
reactions.
From the Table, it was shown that 3-substituted benzo-
furans were obtained in medium to good yield (up to 91%,
Table 4, entry 11). Aryl ketones were obtained as a byproduct
in some cases (Table 4, entries 2, 3, 5, 7, 9, and 17) implying
that the reaction may proceed with the addition of arylboronic
acids to nitriles as the first step. A higher yield was obtained
using R-substituted 3,5-dimethoxyphenoxyacetonitrile (4b)
as the substrate than that using 4a (Table 4, compare entries
1 and 6). Catalyst C is more effective than catalyst B in this
reaction. Using phenoxyacetonitrile as the substrate, only 3o
was isolated in 91% yield (Table 3, entry 15) implying that
the activation of the benzene ring with three alkoxy groups
is necessary in this reaction. Using Pd(OAc)2 as the catalyst,
no formation of benzofuran occurred, but only the ketone
product 6 could be isolated.
Benzofuran derivatives are an important class of hetero-
cyclic compounds that are known to possess important
biological properties.13 In the literature, several methods were
reported for the preparation of 3-substituted benzofurans from
Acknowledgment. We thank the National Natural Sci-
ences Foundation of China (20572121) and the Chinese
Academy of Sciences for financial support.
(13) See, for example: Buu-Ho¨ı, N. P. Ph.; Bisagni, E.; Royer, R.;
Routier, C. J. Chem. Soc. 1957, 625.
(14) (a) Black, D. S. C.; Craig, D. C.; Kumar, N.; Rezaie, R. Tehrahedron
1999, 55, 4803. (b) Dehmlow, H.; Aebi, J. D.; Jolidon, S.; Ji, Y.-H.; von
der Mark, E. M.; Himber, J.; Morand, O. H. J. Med. Chem. 2003, 46, 3354.
(c) Guthrie, R. W.; Kaplan, G. I.; Mennona, F. A.; Tilley, J. W.; Kierstead,
R. W.; O’Donnell, M.; Crowley, H.; Yaremko, B.; Welton, A. F. J. Med.
Chem. 1990, 33, 2856. (d) Hambermann, J.; Ley, S. V.; Smits, R. J. Chem.
Soc., Perkin Trans. 1 1999, 2421. (e) Meshram, H. M.; Sekhar, K. C.;
Ganesh, Y. S. S.; Yadav, J. S. Synlett 2000, 1273.
Supporting Information Available: Experimental pro-
cedures and characterization data of new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL062438V
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Org. Lett., Vol. 8, No. 26, 2006