1056
¹
[Ir(cod)2]+BF4 showed low or no catalytic activities (Entries
3-7). As expected, no 3a was formed in the absence of an Ir
complex. The alkylation was extensively influenced by the base
employed. Strong bases such as t-BuOK and KOH were found
to be suitable bases (Entries 1 and 8). However Cs2CO3 was
inert in this alkylation, and no reaction was induced in the
absence of a base (Entries 9 and 10). The addition of smaller
amounts of t-BuOK resulted in considerably decreased yields of
3a (Entry 11). When the amount of t-BuOK was increased, 3a
was obtained in a slightly lower yield (Entry 12). These results
indicate that this reaction was efficiently promoted by the
addition of a catalytic amount (10 mol %) of a base, and t-BuOK
was found to be the most suitable base. Another important
feature of the present reaction was the ratio of 1 to 2a. Among
the substrate ratios examined, the best result was obtained using
an excess (10 equiv) of 1 with respect to 2a. This significantly
affected the yield of 3a (Entry 1 vs. Entry 13). In this reaction,
the highest catalytic activity was attained using [Ir(OH)(cod)]2 in
combination with triphenylphosphine (PPh3) as a ligand. Other
selected phosphine ligands such as tricyclohexylphosphine
(Cy3P) and bidentate phosphine ligands such as 1,2-bis(diphen-
ylphosphino)ethane (dppe) were found to have low catalytic
activities (Entries 15 and 16). The optimized reaction temper-
ature was 130 °C, and the reaction at 100 °C resulted in a con-
siderable decrease (11%) in the yield of 3a. Among the solvents
examined, 1,4-dioxane was found to be the best solvent. Under
the reaction conditions in Entry 1, Table 1, the yields of 3a in
various solvents were as follows: p-xylene 58%, n-octane 28%,
DMSO 13%, toluene 8%, and solvent-free conditions 47%.
Table 2 shows the alkylation of 1a with various alcohols
under the same conditions as in Entry 1, Table 1. The reaction of
1a with aliphatic alcohols, i.e., n-butanol (2b), n-octanol (2c),
and n-hexadecanol (2d), afforded the corresponding nitriles, 3b,
3c, and 3d, in 55%, 72%, and 80% yields, respectively (Entries
1-3). Similarly, 1 was efficiently alkylated with cyclohexyl-
methanol (2e) to give 3e in good yield (83%) (Entry 4). The
alkylation of 1a with various 4-substituted benzyl alcohols, 2f-
2i, gave rise to the corresponding phenethyl cyanides, 3f-3i, in
high to excellent yields (77-95%) (Entries 5-8). 2-Naphthyl-
methanol (2j) gave the corresponding product 3j in substantial
yield (Entry 9).
Table 2. Ir-catalyzed reaction of acetonitrile (1) and primary
and secondary alcohols 2a
cat. [Ir(OH)(cod)]2 / PPh3
R2
R2
cat. t-BuOK
CH3CN
+
CN
R1
OH
R1
1,4-Dioxane
1
2
3
Alcohol 2
Entry
2
3
Yield/%b
R1
R2
1
n-C3H7
n-C7H15
n-C15H31
c-C6H11
C6H5
p-CH3-C6H4
p-t-Bu-C6H4
p-CH3O-C6H4
2-Nap
H
H
H
H
H
H
H
H
2b
2c
2d
2e
2f
2g
2h
2i
2j
2k
2l
2m
2n
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
3o
3p
55
72
80
83
77
94
95
92
83
76
82
88
69
48
51
c
2c
3d
4e
5
6
7
8e
9
10f,g,h
11f,g,h
12f,g,h
13f,i,j
14f,i,k
15l
H
CH3
n-C4H9
c-C6H11-OH
C6H5-(CH2)2
C6H5
CH3
CH3
C6H5 2o
2p
C6H5
OH-(CH2)10-OH
aConditions: same as Entry 1, Table 1. Isolated yields. For
7 h. dFor 36 h. eFor 15 h. f[Ir(OH)(cod)]2 (0.10 mmol) and PPh3
(0.4 mmol) were used. t-BuOK (0.20 mmol) was used. For
24 h. iFor 48 h. jt-BuOK (0.30 mmol) was used. kt-BuOK
b
g
h
l
(0.40 mmol) was used. Reaction carried out at 200 °C for
7 min under microwave irradiation. Microwaves were irradi-
ated using a Biotage Initiator· in 2 mL vial. Power varied
automatically between 0-100 W to maintain temperature.
CN
R
OH
R
R
2
3
LnIr
[LnIrH]
B
O
Aldol condensation
CN
R
H
In contrast to the previously reported ¡-alkylation reactions
developed by our group, the present reaction proceeded with
secondary alcohols as substrates (Entries 10-14).11a-11e In the
case of the reaction with ¡,½-diol 2p under microwave
irradiation, ¡,½-dinitrile 3p was formed in 51% yield (Entry 15).
The reaction mechanism may be explained by the following
pathway (Scheme 1). The ¡-alkylation reaction is thought to
proceed by sequential reactions, involving three key steps,
similar to the mechanism proposed in a recent review:10 (i)
hydrogen transfer from alcohol 2 to an Ir complex, giving
aldehyde A and an Ir-hydride intermediate B,10,16 (ii) a base-
catalyzed aldol condensation between the resulting acetonitrile 1
to form ¡,¢-unsaturated ketone C, and (iii) hydrogenation of C
by an Ir-hydride complex generated during the course of the
reaction, leading to the ¡-alkylated nitrile 3.
A
C
CH3CN
H2O
1
Base
Scheme 1. Plausible reaction mechanism.
This work was supported by a Grant-in-Aid for Scientific
Research from the Ministry of Education, Culture, Sports,
Science and Technology, Japan, and the Strategic Project to
Support the Formation of Research Bases at Private Universities
(2010-2014), matching fund subsidy from the Ministry of
Education, Culture, Sports, Science and Technology, and the
Kansai University Research Grants: Grant-in-Aid for Encour-
agement of Scientists, 2011.
In conclusion, we developed a novel method for the Ir-
catalyzed alkylation of acetonitrile with alcohols, providing a
clean and atom-economical industrial route to various substi-
tuted nitriles.17
This paper is in celebration of the 2010 Nobel Prize
awarded to Professors Richard F. Heck, Akira Suzuki, and
Ei-ichi Negishi.
Chem. Lett. 2011, 40, 1055-1057
© 2011 The Chemical Society of Japan