Palladium-catalyzed reaction of arylboronic acids with aliphatic nitriles: Synthesis of alkyl aryl ketones and 2-arylbenzofurans

Article abstract of DOI:10.1055/s-0033-1338909

An efficient palladium-catalyzed addition of arylboronic acids to aliphatic nitriles has been developed, providing a wide range of alkyl aryl ketones in moderate to excellent yields. It is noteworthy that sequential addition and intramolecular annulation reaction of 2-(2-hydroxyphenyl)acetonitriles with arylboronic acids are also conducted smoothly to afford 2-arylbenzofurans in good yields under the standard conditions. Georg Thieme Verlag Stuttgart. New York.

Full text of DOI:10.1055/s-0033-1338909

PAPER
▌2241
paper
Palladium-Catalyzed Reaction of Arylboronic Acids with Aliphatic Nitriles:
Synthesis of Alkyl Aryl Ketones and 2-Arylbenzofurans
Synthesis of Alkyl Aryl Ketones from Nitriles
Xingyong Wang,a Xiaodong Wang,a Miaochang Liu,*a Jinchang Ding,a,b Jiuxi Chen,*a Huayue Wua
a
College of Chemistry and Materials Engineering, Wenzhou University, Wenzhou, 3250235, P. R. of China
Fax +86(577)88368280; E-mail: jiuxichen@wzu.edu.cn; E-mail: mcl@wzu.edu.cn
b
Wenzhou Vocational and Technical College, Wenzhou, 325035, P. R. of China
Received: 31.03.2013; Accepted after revision: 29.04.2013
As part of the continuing efforts in our laboratory towards
Abstract: An efficient palladium-catalyzed addition of arylboronic
the development of novel transition metal-catalyzed reac-
acids to aliphatic nitriles has been developed, providing a wide
tions under participation of organoboron reagents,9 we
herein report a new method for the synthesis of alkyl aryl
range of alkyl aryl ketones in moderate to excellent yields. It is note-
worthy that sequential addition and intramolecular annulation reac-
tion of 2-(2-hydroxyphenyl)acetonitriles with arylboronic acids are ketones by palladium-catalyzed addition of arylboronic
also conducted smoothly to afford 2-arylbenzofurans in good yields
under the standard conditions.
acids to aliphatic nitriles (Scheme 1). Furthermore, the
scope of the developed approach is successfully explored
Key words: palladium, aliphatic nitriles, arylboronic acids, alkyl
aryl ketones, 2-arylbenzofurans
toward one-step synthesis of 2-arylbenzofurans via se-
quential addition and intramolecular annulation reaction.
O
RCN
Generally, the nitrile group is inert in organometallic re-
actions and thus acetonitrile or benzonitrile are usually
used as solvents or ligands in many metal-catalyzed reac-
tions. However, transformations of nitriles play an impor-
tant role in both the laboratory and industry due to their
well-recognized chemical versatility.1 Transition-metal-
catalyzed insertion of nitriles offers an attractive route for
the creation of novel carbon–carbon and carbon–heteroat-
om bonds. Recently, a few examples of rhodium,2 palladi-
um,3 and nickel-catalyzed4 additions of arylboronic acids
to nitriles became known; however, the substrate scope
is usually limited to aromatic nitriles, and activated ni-
triles [e.g., cyanoformate2b and (benzyl-/arylsulfo-
nyl)acetonitriles2c]. Compared to the reactions of aromatic
nitriles, one of the main problems encountered in nucleo-
philic addition reactions of aliphatic nitriles is the insuffi-
cient electrophilic activation to perform the addition. On
the other hand, aliphatic nitriles tend to be deprotonated in
the presence of palladium catalysts leading to α-arylation
products.5 Thus, the addition reaction of aliphatic nitriles
is generally more challenging than that of aromatic ni-
triles.
The insertions of nitrile groups by Grignard reagents6 and
organolithium reagents7 are powerful tool for the con-
struction of aryl ketones and heterocyclic compounds;
however, the rigorous conditions have sometimes restrict-
ed their applications and the variety of substrates. Com-
pared to the reactions using Grignard reagents and
organolithium reagents, organoboron reagents are highly
regarded due to their advantages of stability to air and
moisture as well as good functional group tolerance.8
Ar
R
R = alkyl
ArB(OH)2
CN
R
OH
Ar
R
O
Scheme 1 Palladium-catalyzed reaction of arylboronic acids with
aliphatic nitriles
To optimize the reaction conditions, initial studies were
concentrated on treatment of acetonitrile (1a) with
phenylboronic acid (2a) as a model reaction. As shown in
Table 1, the best result was observed with palladium(II)
acetate as the catalyst in the presence of 2,2′-bipyridine
(bpy) in this transformation (Table 1, entry 9). In contrast,
the yield of the desired product 3a was decreased to some
extent when the reactions were carried using other palla-
dium sources in tetrahydrofuran (entries 1–7). On the oth-
er hand, the effect of solvents was also tested. Among all
the solvents screened (e.g., THF, 1,4-dioxane, DMSO,
DMF, toluene, and xylenes), tetrahydrofuran was deter-
mined to be the most effective medium for the generation
of 3a (entries 9–14). Then, various acids were screened as
the additive to examine their effect on the reaction.
Screening revealed that various additives, including acetic
acid, trifluoromethanesulfonic acid, p-toluenesulfonic
acid, and benzoic acid were less effective than trifluoro-
acetic acid (entries 15–18). It was one of the major reasons
that the use of trifluoroacetic acid as additive facilitates
the generation of highly cationic [Pd(II)O2CCF3]10 spe-
cies to form palladium–aryl complexes through trans-
metalation of arylboronic acids.
Having the optimized reaction conditions in hand, we ex-
plored the substrate scope of aliphatic nitriles and arylbo-
ronic acids for this transformation (Table 2). Initially, the
SYNTHESIS 2013, 45, 2241–2244
Advanced online publication: 11.06.2013
DOI: 10.1055/s-0033-1338909; Art ID: SS-2013-F0255-OP
© Georg Thieme Verlag Stuttgart · New York
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X

2242
X. Wang et al.
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Table 1 Screening for Optimal Reaction Conditionsa
(2j) also afforded the corresponding 3h, 3i, and 3j in 81%,
87%, and 82% yield, respectively (entries 8–10).
O
Pd source, bpy
Subsequently, other aliphatic nitriles bearing α-alkyl sub-
stituents (e.g., 1b–e) or α-aryl substituents (e.g., 1f–i)
were evaluated (Table 2, entries 11–18). The results dis-
closed that primary α-alkylnitriles, such as pentanenitrile
(1b) and octanenitrile (1c), are suitable substrates, leading
to the corresponding products in good yields (entries 11,
12). The transformation of secondary α-alkylnitriles, such
as isobutyronitrile (1d) or cyclopropylnitrile (1e) with 2a
also proceeded successfully to provide the respective
products in 84% and 83% yield, respectively (entries 13,
14). Excellent yields were observed when α-aryl substitut-
ed nitriles 1f–h bearing either an electron-rich phenyl or
electron-deficient phenyl group were used as substrate
(entries 15–17). Interestingly, treatment of 2-(2-hydroxy-
phenyl)acetonitrile (1i) with 2a under the standard condi-
PhB(OH)2
MeCN
+
Ph
additive, solvent
1a
2a
3a
Entry Pd source
Additive
Solvent
Yield (%)b
1
2
Pd(PPh3)4
Pd2(dba)3
Pd(dba)2
CF3CO2H
CF3CO2H
CF3CO2H
CF3CO2H
CF3CO2H
CF3CO2H
CF3CO2H
CF3CO2H
CF3CO2H
CF3CO2H
CF3CO2H
CF3CO2H
CF3CO2H
CF3CO2H
CF3CO2H
PhCO2H
THF
THF
THF
THF
THF
THF
THF
THF
THF
trace
trace
trace
trace
trace
trace
48
3
4
PdCl2(dppe)
PdCl2(PPh3)2
PdCl2
5
6
7
Pd(acac)2
Pd(TFA)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
8
83
Table 2 Palladium-Catalyzed Synthesis of Alkyl Aryl Ketonesa
9
88
O
Pd(OAc)2 (5 mol%)
10
11
12
13
14
15
16
17
18
1,4-dioxane 71
ArB(OH)2
RCN
+
R
Ar
bpy, TFA, THF–H2O
N2, 80 °C, 36 h
DMSO
DMF
25
0
1
2
3
Entry 1
R
2
Ar
Product Yield
(%)b
toluene
xylenes
THF
41
37
12
14
72
42
1
2
1a
1a
Me
2a
2b
2c
2d
2e
2f
Ph
3a
3b
3c
3d
88
89
83
51
93
75
67
81
87
82
94
96
84
83
97
92
99
94c
Me
4-MeC6H4
3-MeC6H4
2-MeC6H4
THF
3
1a
1a
1a
1a
1a
1a
1a
1a
1b
1c
1d
1e
1f
Me
CF3SO3H
THF
4
Me
4-MeC6H4SO3H THF
5
Me
4-MeOC6H4 3e
a Reaction conditions: 1a (0.4 mmol), 2a (0.8 mmol), Pd source (5
mol%), bpy (10 mol%), additive (10 equiv), solvent (2 mL), H2O (0.4
mL), 80 °C, 36 h, N2.
6
Me
4-ClC6H4
4-BrC6H4
4-PhC6H4
3f
7
Me
2g
2h
2i
3g
3h
b Isolated yield.
8
Me
9
Me
1-naphthyl 3i
2-naphthyl 3j
reaction between acetonitrile (1a) and various arylboronic
acids 2b–j was investigated under the standard conditions
(Table 2, entries 1–10). As shown in Table 2, the mono-
substituent positions at the aryl moiety of arylboronic ac-
ids were evaluated, and the results demonstrated that
steric effects of substituents affected the yields of the re-
action to some extent. For example, the coupling of 1a
with 4-, 3- and 2-tolylboronic acid was examined, 89% of
3b and 83% of 3c were isolated, while the yield of 3d was
decreased to 51% (entries 2–4). In general, the arylboron-
ic acids possessing electron-donating groups afforded a
higher yield than electron-withdrawing arylboronic acids.
For example, substrates 2e and 2f, bearing a 4-methoxy-
phenyl or 4-chlorophenyl group, reacted with substrate 1a
to give the corresponding products in 93% and 75% yield,
respectively (entries 5, 6). It is noteworthy that biarylbo-
ronic acids such as 4-phenylphenylboronic acid (2h), 1-
10
11
12
13
14
15
16
17
18
Me
2j
n-Bu
n-C7H15
i-Pr
2a
2a
2a
2a
2a
2a
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
3k
3l
3m
3n
3o
3p
3q
4a
c-Pr
Bn
1g
1h
1i
4-MeC6H4CH2
4-O2NC6H4CH2 2a
2-HOC6H4CH2 2a
a Unless otherwise noted, reaction conditions were as follows: 1 (0.4
mmol), 2 (0.8 mmol), Pd(OAc)2 (5 mol%), bpy (10 mol%), TFA (10
equiv), THF (2 mL), H2O (0.4 mL), 80 °C, 36 h, N2.
naphthylboronic acid (2i), and 2-naphthylboronic acid b Isolated yield.
c 2-Phenylbenzofuran was obtained in 94% yield.
Synthesis 2013, 45, 2241–2244
© Georg Thieme Verlag Stuttgart · New York

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Synthesis of Alkyl Aryl Ketones from Nitriles
2243
Table 3 Palladium-Catalyzed Synthesis of 2-Arylbenzofuransa
tions afforded the unexpected 2-phenylbenzofuran (4a) in
94% yield instead of alkyl aryl ketone product (entry 18).
CN
+
Pd(OAc)2 (5 mol%)
R
R
Ar
ArB(OH)2
Benzofurans are abundant in numerous natural products
and possess many important biological activities.11 As an
application of our chemistry, we next explored a simple
and efficient approach to other 2-arylbenzofurans, which
involves ketone formation from the addition of 2-hy-
droxyphenylacetonitriles with arylboronic acids, followed
by intramolecular cyclization under mild conditions. As
shown in Table 3, the electronic properties of the groups
on the phenyl ring of arylboronic acids had some effect on
the reaction. Electron-rich arylboronic acids with a methyl
or methoxy group at the para position proved to be good
substrates for this transformation, affording the corre-
sponding 2-arylbenzofurans 4b and 4c in higher yields
(Table 3, entries 2, 3). Having an electron-withdrawing
substituent (e.g., fluoro, chloro, bromo, and phenyl) at the
para position afforded a slightly lower yield of the desired
products 4d–g (entries 4–7). Notably, the fluoro, chloro,
and bromo moieties (commonly used for cross-coupling
reactions) in arylboronic acids were all tolerated and af-
forded a novel route to compounds 4d–f in good yields,
making further elaborations of the corresponding biaryl-
benzofuran derivatives possible.
bpy, TFA, THF–H2O
N2, 80 °C, 36 h
OH
O
1
2
4
Entry 1
R
2
Ar
Product Yield (%)b
1
2
1i
H
H
H
H
H
H
H
2a
2b
2e
2k
2f
Ph
4a
4b
94
91
92
86
84
81
85
91
89
81
80
1i
1i
1i
1i
1i
1i
4-MeC6H4
3
4-MeOC6H4 4c
4
4-FC6H4
4-ClC6H4
4-BrC6H4
4-PhC6H4
Ph
4d
4e
4f
5
6
2g
2h
7
4g
4h
4i
8
1j
4-Me
2a
9
1k
1l
3-MeO 2a
Ph
10
11
4-Cl
4-Br
2a
2a
Ph
4j
1m
Ph
4k
a Reaction conditions: 1 (0.4 mmol), 2 (0.8 mmol), Pd(OAc)2 (5
mol%), bpy (10 mol%), TFA (10 equiv), THF (2 mL), H2O (0.4 mL),
80 °C, 36 h, N2.
Next, the addition reactions of several 2-hydroxyphenyl-
acetonitriles with phenylboronic acid (2a) were investi-
gated. As expected, the groups on the phenyl ring of 2-
hydroxyphenylacetonitriles, such as methyl, chloro,
bromo, and methoxy, were quite compatible under the op-
timized reaction conditions. Generally, 2-hydroxyphenyl-
acetonitriles having an electron-donating substituent (e.g.,
methyl and methoxy) on the phenyl group (Table 3, en-
tries 8, 9) gave a slightly higher yield of the desired 2-ar-
ylbenzofurans than those analogues bearing electron-
withdrawing substituent (e.g., chloro and bromo; entries
10, 11).
b Isolated yield.
Alkyl Aryl Ketones 3 and 2-Arylbenzofurans 4; General Proce-
dure
To a Schlenk tube with a magnetic stirring bar were charged the re-
spective nitrile 1 (0.4 mmol), arylboronic acid 2 (0.8 mmol),
Pd(OAc)2 (5 mol%), bpy (10 mol%), TFA (10 equiv), THF (2 mL),
and H2O (0.4 mL) under N2 atmosphere. The reaction mixture was
stirred at 80 °C for 36 h. After cooling to r.t., the mixture was
poured into EtOAc (5 mL), which was washed with sat. aq NaHCO3
(2 × 10 mL) and then brine (1 × 10 mL). After extracting the aque-
ous layer with EtOAc (3 × 10 mL), the combined organic layers
were dried (Na2SO4), and evaporated under vacuum. The residue
was purified by flash column chromatography (hexane–EtOAc) to
afford the desired products 3 or 4. All known compounds afforded
analytical data identical to those reported literature previously (see
Supporting Information for further details).
In summary, we have developed a new catalytic protocol
to synthesize alkyl aryl ketones by palladium-catalyzed
addition reaction of arylboronic acids with aliphatic ni-
triles in moderate to excellent yields. The scope of this
chemistry is successfully explored toward one-step syn-
thesis of 2-arylbenzofurans via sequential addition and in-
tramolecular annulation reaction. Investigations on the
further applications in the future for rapidly constructing
other useful heterocyclic compounds are currently under-
way in our laboratory.
Acetophenone (3a)
Yield: 42.3 mg (88%); colorless oil.
1H NMR (500 MHz, CDCl3): δ = 7.96 (d, J = 7.1 Hz, 2 H), 7.57 (t,
J = 7.4 Hz, 1 H), 7.47 (t, J = 7.4 Hz, 2 H), 2.61 (s, 3 H).
13C NMR (125 MHz, CDCl3): δ = 198.2, 137.2, 133.1, 128.6, 128.3,
26.6.
All chemicals were either purchased or purified by standard tech-
niques. Melting points were measured on Digital Melting Point Ap-
2-Phenylbenzo[b]furan (4a)
Yield: 72.9 mg (94%); white solid; mp 119−120 °C.
1H NMR (500 MHz, CDCl3): δ = 7.86 (d, J = 7.4 Hz, 2 H), 7.57 (d,
J = 7.6 Hz, 1 H), 7.52 (d, J = 8.1 Hz, 1 H), 7.43 (t, J = 7.8 Hz, 2 H),
7.34 (t, J = 7.4 Hz, 1 H), 7.28 (t, J = 7.6 Hz, 1 H), 7.22 (t, J = 7.4
Hz, 1 H), 7.10 (s, 1 H).
1
paratus WRS-1B and are uncorrected. H NMR and 13C NMR
spectra were recorded on a 500 MHz Bruker spectrometer (1H 500
MHz and 13C 125 MHz), using CDCl3 or DMSO-d6 as the solvent
with TMS as the internal standard at r.t. Chemical shifts are given
in δ relative to TMS, the coupling constants J are given in Hz. Col-
umn chromatography was performed using EM Silica gel 60 (300–
400 mesh).
13C NMR (125 MHz, CDCl3): δ = 156.0, 154.9, 130.5, 129.3, 128.8,
128.6, 125.0, 124.3, 123.0, 120.9, 111.2, 101.3.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 2241–2244

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X. Wang et al.
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Acknowledgment
We thank the National Natural Science Foundation of China (No.
21102105) and Natural Science Foundation of Zhejiang Province
(No. LY12B02011) for financial support.
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Synthesis 2013, 45, 2241–2244
© Georg Thieme Verlag Stuttgart · New York