Synthesis of alkylated nitriles by [RuHCl(CO)(PPh3) 3]-catalyzed alkylation of acetonitrile using primary alcohols

Article abstract of DOI:10.1246/cl.130465

Alkylation reaction of acetonitrile using primary alcohols is effectively catalyzed by [RuHCl(CO)(PPh₃)₃] in the presence of K ₃PO₄ as a base. Both benzylic and non-benzylic alcohols coupled with acetonitrile to give alkylated nitriles in good yields.

Full text of DOI:10.1246/cl.130465

doi:10.1246/cl.130465
Published on the web June 8, 2013
1163
Synthesis of Alkylated Nitriles by [RuHCl(CO)(PPh ) ]-catalyzed Alkylation
3
3
of Acetonitrile Using Primary Alcohols
Takashi Kuwahara, Takahide Fukuyama,* and Ilhyong Ryu*
Department of Chemistry, Graduate School of Science, Osaka Prefecture University, Sakai, Osaka 599-8531
(
Received May 17, 2013; CL-130465; E-mail: ryu@c.s.osakafu-u.ac.jp, fukuyama@c.s.osakafu-u.ac.jp)
Alkylation reaction of acetonitrile using primary alcohols
is effectively catalyzed by [RuHCl(CO)(PPh3)3] in the presence
of K3PO4 as a base. Both benzylic and non-benzylic alcohols
coupled with acetonitrile to give alkylated nitriles in good
yields.
O
OH
[RuHCl(CO)(PPh
3
)
3
]
O
(
Ref. 9)
+
R1
R2
Cs CO
R1
R2
2
3
ketone
O
O
OH
[RuHCl(CO)(PPh3)3]
KO Bu
R3
R3
N
R3
+
+
N
R3
R2
(Ref. 10)
R2
t
The nitrile moiety is intrinsically important in organic
synthesis, since it can be transformed to a variety of functional
acetamide
OH
R2
[RuHCl(CO)(PPh ) ]
3 3
1
MeCN
NC
This Work
R2
groups including amides, amines, and carboxylic acids. The
K PO
3
4
most common protocol for alkylated nitrile synthesis is
acetonitrile
2
substitution of alkyl halides by cyanide ion. However, cyanide
Scheme 1. [RuHCl(CO)(PPh3)3]-catalyzed ¡-alkylation using
primary alcohols.
reagents, such as KCN and NaCN, are highly toxic and therefore
careful handling is required for their use. Alkylation of
acetonitrile using organic halides can provide an alternative
Table 1. Optimization of the reaction conditionsa
method for the synthesis of nitriles.3 While in this protocol
[
RuHCl(CO)(PPh ) ]
3 3
acetonitrile can serve as a C2 nitrile source, it inevitably forms a
stoichiometric amount of inorganic salts as by-product.
OH
(3 mol %)
+
NC
MeCN
Ph
In the past decade, in pursuit of a greener reaction process,
transition-metal-catalyzed alkylation reaction of carbonyl and
related compounds using primary alcohols has been pursued
Ph
2a
base, bath temp, time
1
3a
b
Entry Base (equiv)
Temp/°C
Time/h
Yield /%
4
vigorously by several groups including us. In these method-
1
2
3
4
5
6
KOt-Bu (1.1)
Cs2CO3 (1.1)
K3PO4 (1.1)
K3PO4 (1.1)
110
110
110
90
110
110
20
20
20
20
5
0
61
76 (67)
49
27
ologies, alcohols have been transformed to aldehydes in situ via
metal-catalyzed dehydrogenation, then the latent aldehydes act
as electrophiles for C­C bond formation, in which only water is
the by-product. While a variety of metal complexes have been
K PO (1.1)
5
3
4
used for ¡-alkylation of ¡-functionalized acetonitriles, as for
K3PO4 (0.5)
20
21
alkylation of the parent acetonitrile only Ir complexes have been
a
6
,7
Conditions: 2a (1 mmol), [RuHCl(CO)(PPh3)3] (3 mol %),
examined.
Cossy and co-workers reported alkylation of
b
base, MeCN (1) (1.5 mL). NMR yield. Isolated yield is shown
in parenthesis.
acetonitrile using primary alcohols catalyzed by [IrCl(cod)]2
under microwave irradiation.6 Obora’s group used [Ir(OH)-
7
(
[
cod)]2 for the alkylation of acetonitrile. Since we found that
RuHCl(CO)(PPh3)3],8 combined with the use of nitrogen
The use of a reduced amount of K3PO4 also caused the decrease
in the yield of 3a (Entry 6).
ligands, effectively catalyzed the ¡-alkylation reaction of
9
10
ketones and acetamides using primary alcohols (Scheme 1),
we were motivated to examine the same catalyst for ¡-alkylation
of acetonitrile. In this paper, we report that [RuHCl(CO)(PPh ) ]
Having the optimized conditions of Entry 3 in hand, we
then examined the generality of the alkylation reaction of
acetonitrile (1). The results are summarized in Table 2. The
reaction of 1 with substituted benzyl alcohols 2b­2f, gave
the corresponding 3-arylpropanenitriles 3b­3f in good yields
(Entries 2­6). The reaction of non-benzylic alcohols, cyclo-
hexanemethanol (2g) also gave the corresponding nitrile 3g but
in lower yield. The use of higher temperature of 140 °C gave 3g
in 75% yield (Entry 7). Using similar conditions alkylation of 1
with 3-phenylpropanol (2h) gave 5-phenylpentanenitrile (3h) in
70% yield (Entry 8).
To gain insight into the reaction mechanism, we conducted
control experiments (Scheme 2). The reaction of acetonitrile (1)
and benzaldehyde (4) leading to cinnamonitrile (5) was inves-
tigated under basic conditions. Regardless of the Ru­H complex,
5 was formed in similar yields (eq 1). This suggests that the
Ru­H complex would not play a special role in the C­C bond-
3
3
is indeed an effective catalyst even for the ¡-alkylation reaction
of acetonitrile using primary alcohols.
The alkylation of acetonitrile (1) was investigated with
benzyl alcohol (2a) as a test alcohol (Table 1). When the
reaction of 1 (1.5 mL) with 2a (1 mmol) was carried out in the
presence of [RuHCl(CO)(PPh3)3] (3 mol %) and KOt-Bu
(1.1 equiv) as a base at 110 °C for 20 h, no alkylated product
was obtained (Entry 1). When we used Cs2CO3 as a base, the
desired alkylated product 3a was obtained in 61% yield
(
Entry 2). It was found that K PO was further more effective
3 4
to give 76% yield of 3a (Entry 3). Either lowering the
temperature to 90 °C (Entry 4) or shorter reaction time of 5 h
(Entry 5) resulted in lower conversions, in which a significant
amount of benzyl alcohol (2a) was recovered (Entries 4 and 5).
Chem. Lett. 2013, 42, 1163­1165
© 2013 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/

1164
Table 2. [RuHCl(CO)(PPh ) ]-catalyzed alkylation of aceto-
nitrile (1) using primary alcohols 2
[RuHCl(CO)(PPh
(3 mol %)
) ]
3 3
3
3
a
O
+
NC
(1)
MeCN
Ph
K PO 1.1 equiv
H
Ph
3
4
[
RuHCl(CO)(PPh ) ]
3 3
110 °C (bath temp), 20 h
OH
(3 mol %)
1
4
5
+
NC
MeCN
R1
R1
K PO 1.1 equiv
with
[RuHCl(CO)(PPh
3
3
)
)
3
] 15%
] 12%
3
4
1
2
110 °C (bath temp), 20 h
Product 3
NC
3
without [RuHCl(CO)(PPh
3
b
Entry
Alcohol 2
OH
Yield /%
[
RuHCl(CO)(PPh ) ]
3 3
OH
Ph
(3 mol %)
NC
+
NC
(2)
Ph
Ph
1
67
K PO 1.1 equiv
Ph
3
4
Ph
110 °C (bath temp), 20 h
5
2a
3a
2a
3a
with
[RuHCl(CO)(PPh ) ] 13%
3 3
OH
OH
NC
NC
without [RuHCl(CO)(PPh
)
]
0%
3
3
2
83
76
Ph
Ph
Scheme 2. Control experiments.
2
b
c
3b
3c
[RuHCl(CO)(PPh ) ] + 2a
3
3
3c,d
tBu
K3PO4
tBu
2
[Ru]
O
OH
NC
NC
Ph
Ph
4
73
75
3
a
O
A
OMe
OMe
2d
3d
3e
H
Ph
OH OMe
OMe
[Ru]
H
MeCN
5c,d
NC
B
K PO
3 4
H O
2
e
2
OH
Ph
OH
NC
OMe
NC
Ru]
Ph
6c,d
OMe
71
NC
Ph
2a
[
5
C
2f
3f
OH
Scheme 3. Possible reaction mechanism.
7c
8c
NC
75
70
Cy
Cy
2
2
g
h
3g
3h
undergo protonolysis by alcohol 2a to give ¡-alkylated nitrile 3a
and alkoxoruthenium A, thus creating the catalytic cycle.
In summary we have found that the alkylation reaction of
acetonitrile with primary alcohols can be effectively catalyzed
by [RuHCl(CO)(PPh3)3] as a catalyst and K3PO4 as a base. The
reaction is useful to obtain higher nitriles from readily available
OH
NC
Ph
Ph
aConditions: Alcohol
3 mol%), K3PO4 (1.1equiv), MeCN (1.5mL), 110°C for 20 h.
2 (0.5mmol), [RuHCl(CO)(PPh3)3]
11
(
reagents and catalyst.
b
c
d
Isolated yields. 140 °C. [RuHCl(CO)(PPh3)3] (5 mol %).
This work was supported by a Grant-in-Aid for Scientific
Research from the MEXT and the JSPS.
forming step. The reaction of 3-phenyl-substituted acrylonitrile
with 1 equiv of benzyl alcohol (2a) was also carried out with
5
or without the Ru­H catalyst (eq 2). Only with the Ru­H
complex, 3a was formed. These results confirmed that the Ru­H
should affect the transfer hydrogenation of unsaturated nitriles
by alcohols.
Taking these observations into consideration, the plausible
reaction mechanism is shown in Scheme 3. An alkoxoruthenium
complex A would be formed in situ from [RuHCl(CO)(PPh3)3]
and an alcohol 2a, which would then afford Ru­H B via ¢-
hydride elimination to give an aldehyde. The resultant benzal-
dehyde would undergo base-promoted aldol condensation with
acetonitrile to give cinnamonitrile (5). Addition of the ruthenium
hydride B to 5 would give Ru-complex C, which would then
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Chem. Lett. 2013, 42, 1163­1165
© 2013 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/