2012 The Chemical Society of Japan

Bull. Chem. Soc. Jpn. Vol. 85, No. 7, 731745 (2012)

731

Award Accounts

The Chemical Society of Japan Award for Young Chemists for 2010

Nickel/Lewis Acid-Catalyzed Carbocyanation

of Unsaturated Compounds
Yoshiaki Nakao
Department of Material Chemistry, Graduate School of Engineering, Kyoto University,
Katsura, Nishikyo-ku, Kyoto 615-8510
Received March 7, 2012; E-mail: yoshiakinakao@npc05.mbox.media.kyoto-u.ac.jp

Addition reactions of the organic and cyano groups of nitriles through cleavage of the CCN bonds, namely
carbocyanation, have been developed using nickel/Lewis acid (LA) cooperative catalysis. Originally, the reaction was
performed with a nickel catalyst alone and was limited to the use of aryl and allyl cyanides as the nitrile substrates.
By employing LA cocatalysts, the rate of the arylcyanation was accelerated signicantly and the scope of nitriles used in
the reaction across alkynes was expanded to include alkenyl, alkynyl, and alkyl cyanides. The high chemo-, regio-, and
stereoselectivities of the alkynecarbocyanation reactions were highlighted by the syntheses of biologically active
compounds including the synthetic precursor of P-3622 and plaunotol, which possess dened tri- or tetrasubstituted
ethene structures. Intramolecular arylcyanation of alkenes was also achieved by cooperative catalysis. Mechanistic studies
on this particular transformation allowed us to identify several reaction intermediates, which revealed the modes of the
cooperative catalysis derived from nickel- and aluminum-based LA. Intramolecular arylcyanation was achieved in an
enantioselective manner using optically active bidentate phosphorus ligands, aording a protocol to introduce both a
quaternary stereocenter and a cyano functionality without by-product generation.

Introduction
CC bond-forming reactions are among the most important
transformations in organic synthesis. Transition-metal catalysis
has introduced a number of innovative CC bond-forming
reactions by virtue of the unique reactivity associated with
various metallic elements in concert with ligands bound to
the metal center. Cross-coupling reactions and olen metathesis
typically represent the power of transition-metal catalysis to
eect novel and innovative CC bond-forming reactions. The
addition reaction of two organic fragments across an unsaturated
compound via the transition-metal-mediated cleavage of CC
single bonds could be regarded as an ultimate transformation,
because the reaction allows simultaneous formation of two CC
bonds, with no by-product formation (eq 1).1 Nevertheless, the
activation of simple CC single bonds is dicult to achieve due
to inecient overlap of sterically and directionally constrained
CC bonds with d-orbitals of transition metals.1b Successful
examples of such transformations thus far reported relied fully
on the use of three-2 or four-membered-ring3 compounds, in
which the cleavage of CC bonds by transition-metal catalysts
was relatively facile owing to a relief of a ring-strain.4,5 CCN
bonds have also been demonstrated to be activated by various
transition-metal complexes. Two types of CCN bond activation
are available: the oxidative addition of CCN bonds to lowvalent transition-metal complexes,6 and the formation of silyl

isonitrile complexes through cleavage of CCN bonds.7 The

high anity of a cyano group for transition metals, which allows
its coordination to a metal center in either an 1- or 2-fashion,8
acts as a kinetic driving force, whereas the formation of strong
metalCN bonds9 acts as a thermodynamic driving force of the
elementary reaction step. Both reactions have already been
applied to catalytic transformations of nitriles through the
cleavage of CCN bonds.10 For example, the oxidative addition
of CCN bonds is an important process in the second step of
DuPonts adiponitrile process,11 in which 2-methyl-3-butenenitrile isomerizes to 3- and/or 4-pentenenitriles through a allylnickel intermediate generated upon oxidative addition of
the allylic CCN bonds to nickel(0) species.12 More recently, the
nickel-catalyzed cross-coupling reactions of aryl cyanides with
organomagnesium reagents, organozinc reagents, and amines
have been reported to proceed through oxidative addition of the
ArCN bonds.13 The CCN bond activation accompanied by the
formation of silyl cyanides can also be performed in a catalytic
manner, allowing the catalytic conversions of CCN bonds to
CH,14 CC,15 CSi,16 and CB17 bonds.

C + R

metal
catalyst

Given the relatively facile activation of CCN bonds in spite

of their high bond dissociation energies,18 one can imagine

Published on the web June 28, 2012; doi:10.1246/bcsj.20120081

732

Bull. Chem. Soc. Jpn. Vol. 85, No. 7 (2012)

C N

R
C N
C

AWARD ACCOUNTS

C N

[M]

R
C N
R

[M]

[M]

C N

[M] C N

C
R

[M]

C N
R

Scheme 1. A possible catalytic cycle of the carbocyanation

reaction.

the addition reaction of both organic and cyano groups across

unsaturated bonds, carbocyanation reactions, through the activation of the CCN bonds of nitriles by transition-metal complexes (Scheme 1). The rst report of such transformations, by
Takaya and co-workers, showed that the reaction of benzoyl
cyanide with terminal arylacetylenes proceeded to give cyano-,-unsaturated ketones (eq 2).19 The mechanism of
the reaction was elucidated by the authors to include the
initial acylation of the alkyne terminus to give alkynylketones,
which subsequently undergoes hydrocyanation, followed by the
isomerization of the resultant trisubstituted double bond to
give formal cis-benzoylcyanation products. The activation of
carbonylCN bonds by palladium catalysts has recently
been reinvestigated to allow for the inter- and intramolecular
cyanoesterication of alkenes (eq 3)20 and alkynes (eq 4),21
respectively, and the intramolecular cyanocarbamoylation of
alkenes (eq 5).22 Our focus, on the other hand, has been the use
of nickel, for which abundant examples of both stoichiometric
and catalytic CCN activation have been reported.23 We rst
described that the addition of aryl cyanides across alkynes
proceeded in the presence of a catalyst derived from [Ni(cod)2]
and PMe3 (eq 6).24 Subsequently, we reported the arylcyanation
of bicyclic alkenes such as norbornene and norbornadiene
(eq 7),25 the allylcyanation of alkynes (eq 8),26 and the cyanoesterication of 1,2-dienes (eq 9),27 all catalyzed by nickel,
demonstrating that nickel catalysis is highly versatile in the
carbocyanation reactions of unsaturated compounds. Nevertheless, the scope of useful nitriles was dicult to further
expand with the nickel catalyst alone, and the reaction conditions needed improvement in terms of catalyst loading and
reaction temperature. Meanwhile, theoretical calculations for
all the proposed steps of the arylcyanation of alkynes were
investigated by Sakaki and Ohnishi,28 which revealed that
oxidative addition of ArCN bonds to nickel(0) species
proceeded through 2-nitrile- and then 2-arenenickel intermediates A and B, respectively, and that these two steps
represented the highest barrier to be overcome to drive the
arylcyanation reaction (Scheme 2).29 Given a plausible, detailed
catalytic cycle, we proposed to employ a Lewis acid (LA) as

an additive for the arylcyanation reaction. We hoped that the

intermediates and transition states estimated in the rate-limiting
CCN cleavage could be stabilized through cyano-group
coordination to the LA and potentially result in the acceleration
of the oxidative addition of the CCN bonds. Accordingly,
we found that aluminum- and boron-based LAs were eective
cocatalysts which signicantly promoted the arylcyanation
reaction and expanded the scope of the nitriles, as described
herein. Tolman and co-workers already showed that the
oxidative addition of the CCN bond of allyl cyanide was
accelerated by the coordination of the cyano group to a LA.30
More recently, Jones and co-workers quantitatively investigated
the eect of LA on the oxidative addition of allyl cyanide to
a [Ni0(dippe)] species [dippe: 1,2-bis(diisopropylphosphino)ethane] in the presence of BPh3, demonstrating that CCN
activation was favorable both thermodynamically and kinetically over the competitive oxidative addition of the allylic CH
bond of allyl cyanide, which eventually gives the thermodynamically more favored [(dippe)Ni0(2-crotonitrile)].6l
O
Ph

CN
+
p -tol

Pd(OAc)2/PPh3
(20 mol %)
dppb (10 mol %)
ClCH2CH2Cl,
70 C, 65 h

O
+

Ph

O
Ph
H

isomerization

+
O

Ph

p -tol 1%
HCN,
cat. Pd
p -tol
2%
CN
CN

74%

p -tol

O
O

CN [Pd(PPh3)4] (10 mol %)

EtO
+

toluene, 110 C, 3 h

EtO

3
NC
78%

Ph

Ph

[Pd(PPh3)4] (10 mol %)

CN
O

CN

DMF, W, 200 C, 5 min

O
isomerization

Ph
CN
O

80%

[Pd2(dba)3] (2 mol %)
MonoPhos (16 mol %)
DMPU (1.0 equiv)
NBn
O

CN
O

THF, 100 C

N
Bn

CN

72%, 94% ee
O
P N
O

MonoPhos

Y. Nakao

Bull. Chem. Soc. Jpn. Vol. 85, No. 7 (2012)

C N

Ni
Me3P PMe3
TSA B
Ph

Ni

Me3P

Ni
Me3P

PMe3

Ea = 24.4

N
Ph

N
PMe3

kcal mol1

Ni
PMe3
Me3P
TSB C

733

C
Ni

Me3P
Ea = 25.1

kcal mol1

PMe3
C

Scheme 2. The rate-limiting oxidative addition of ArCN bonds to nickel(0) via 2-cyano- and -arenenickel intermediates in the
catalytic cycle of the arylcyanation of alkynes.
F

CN

[Ni(cod)2] (10 mol %)

PMe3 (20 mol %)

Pr

toluene, 100 C, 30 h

Pr

CN
Pr
81%

CN
+

+
Pr

CN
Pr

O
EtO

CN

O NC
81%

[Ni(cod)2] (10 mol %)

P(4-CF3 C6H4)3 (20 mol %)

Pr

Pr
78%

[Ni(cod)2] (10 mol %)

PMe2Ph (20 mol %)

CN
t -Bu

EtO

t -Bu

MeO
[Ni(cod)2] (5 mol %)
MeO
CN ligand (10 mol %)
1a (1.0 mmol)
LA (20 mol %)
+
Pr
Pr
toluene, 50 80 C, 24 h
2a (1.0 mmol)

Entry

CN

CH3CN, 80 C, 8 h

toluene, 50 C, 6 h

Pr

[Ni(cod)2] (5 mol %)
PMe3 (10 mol %)
toluene, 100 C, 21 h

Table 1. Eect of LA Cocatalyst on the Arylcyanation of

2a with 1a

70%

Arylcyanation of Alkynes
The originally developed reaction conditions for the arylcyanation of alkynes suered from low eciency in the
addition reactions of electron-rich aryl cyanides. For example,
the reaction of 4-methoxybenzonitrile (1a) with 4-octyne (2a)
at 80 C for 24 h aorded the corresponding adduct (Z)-3aa
in 36% yield, as estimated by GC (Table 1, Entry 1). More
electron-rich nitriles such as 4-dimethylaminobenzonitrile
did not react at all under these conditions. The addition of
boron- and aluminum-based LA, on the other hand, dramatically promoted the reaction.31 For example, in the presence of a
catalytic amount of AlMe3, the reaction aorded (Z)-3aa in
91% yield accompanied by 6% (E)-3aa, which was derived
from the isomerization of (Z)-3aa under the reaction conditions
(Entry 3). The reaction proceeded smoothly even at 50 C,
to give stereoisomeric mixtures of 3aa in high yields in the
presence of aluminum-based LAs (Entries 48), except for
AlCl3 (Entry 9). The high Lewis acidity of AlCl3 might have
prohibited the turnover of the LA catalyst. The use of milder
boron-based Lewis acids was equally eective and showed no
isomerization of (Z)-3aa (Entries 1013). Again, highly Lewis
acidic BF3 retarded the reaction (Entry 14). In the presence of
LA cocatalysts, the reaction took place in the presence of only

1
2
3
4
5
6
7
8
9
10
11
12
13
14

LA
none
none
AlMe3
AlMe3
AlMe2Cl
AlMe2Cl
AlMeCl2
AlMeCl2
AlCl3
BEt3
BEt3
BPh3
BPh3
BF3OEt2

Temp/C
80
50
80
50
80
50
80
50
80
80
50
80
50
80

CN
Pr
Pr
(Z )-3aa

GC yield/%
(Z)-3aa
(E)-3aa
36
1
7
0
91
6
61
0
79
21
94
1
41
50
82
4
6
0
88
0
82
0
68
0
37
0
1
0

1 mol % of the nickel catalyst with a variety of phosphine

ligands to give (Z)-3aa in modest to good yields (Table 2).
Several catalyst combinations were examined to investigate the
scope of aryl cyanides (Table 3). With the nickel/LA cooperative catalysis, a number of substituents on benzonitrile were
tolerated to give the corresponding adducts in good yields.
Lewis basic substituents such as alkoxycarbonyl and amino
groups did not aect the reaction (Entries 2 and 6). Of
particular note was the exclusive activation of ArCN bonds
by cooperative catalysis over Arhalogen bonds, which are
commonly reacted with electron-rich nickel(0) catalysts, as can
be seen in cross-coupling reactions32 (Entries 35). Highly
sterically demanding benzonitriles (Entries 7 and 8) as well as
heteroaryl cyanides (Entries 9 and 10) reacted with 2a in good
yields. The high chemoselectivity associated with the nickel/
LA cooperative catalyst system allowed for the reaction of 4-

734

Bull. Chem. Soc. Jpn. Vol. 85, No. 7 (2012)

AWARD ACCOUNTS

Table 2. Optimization of Ligand/LA Combinations for the

Reaction of 1a with 2a
MeO
[Ni(cod)2] (1 mol %)
CN ligand (2 mol %)
1a (1.0 mmol)
LA (4 mol %)
+
Pr
Pr
toluene, 50 C, 24 h
2a (1.0 mmol)

Ligand

AlMe3
60
63
95
92
95
29

PMe3
P(n-Bu)3
PPhMe2
PPh2Me
PCy2Me
P(p-An)3a)

MeO

CN
Pr
Pr
(Z )-3aa

LA/GC yield/% of (Z)-3aa/%

AlMe2Cl AlMeCl2 BPh3
88
7
31
41
5
39
>99
8
78
98
<1
92
50
<1
79
6
<1
53

BEt3
9
<1
6
<1
1
1

a) p-An: 4-MeOC6H4.

Table 3. Arylcyanation of Alkynes Catalyzed by Ni/LA

[Ni(cod)2] (1 mol %)
ligand (2 mol %)
LA (4 mol %)

Ar CN
1 (1.0 mmol)
+
R1
R2
2 (1.0 mmol)

Ar

CN

Ar

NC
+

toluene

R1

R2
3

Ar = 4-Me2NC6H4 (1b)
4-FC6H4 (1c)
4-ClC6H4 (1d)
4-BrC6H4 (1e)
4-MeO2CC6H4 (1f)
2-MeOC6H4 (1g)
2,6-Me2C6H3 (1h)
2-thienyl (1i)
1-Me3-indolyl (1j)

Entry

Cond.a)

1
2
3
4
5b)
6
7
8b)
9
10
11
12
13
14
15
16

1a
1b
1c
1d
1e
1f
1g
1h
1i
1j
1d
1d
1d
1d
1d
1d

2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2b
2c
2d
2e
2f
2g

A
A
B
B
A
A
B
A
B
A
C
C
C
C
D
C

R1

R2
3'

R1, R2 = Me (2b)
Me3SiCH2 (2c)
Me, i -Pr (2d)
Me, t -Bu (2e)
Et, p -An (2f)
Me, SiMe3 (2g)

Temp Time
/C
/h 3
50
16 96
80
21 87
50
18 95
50
18 94
50
27 72
80
25 93
80
28 92
100
134 78
50
140 81
50
116 58
60
12 88
60
6 84
60
5 87
60
19 89
60
32 53
80
13 70

Isolated yield/%
3
(3aa)

(3ba)

(3ca)

(3da)

(3ea)

(3fa)

(3ga)

(3ha)

(3ia)

(3ja)

(3db)
(3dc)

(3dd/3dd = 64:36)
(3de/3de = 91:9)
(3df )c) 27 (3df )
(3dg)d) 9 (3dg)

a) Conditions A: PPhMe2/AlMe2Cl; B: PPh2Cy/AlMe3; C:

PPh2(i-Pr)/AlMe2Cl; D: PPh2Me/AlMe2Cl. b) Reaction run
with Ni/PPhMe2/AlMe2Cl = 5/10/20 mol %. c) (E)-Isomer
was also isolated in 5% yield. d) E/Z = 47:53 (78:22 at 5 h).

chlorobenzonitrile (1d) with various internal alkynes (Entries

1116). The observed regioselectivity associated with unsymmetrical alkynes was in accordance with that estimated by
theoretical calculations, which suggested preferable formation
of 3 having a bulkier substituent at the cyano-substituted
carbon through kinetically favored migratory insertion of the
aryl group to the sterically less-hindered carbon of the alkyne
coordinated to the nickel center (Entries 1316).28 Alternative
cyanonickelation was estimated to be unfavorable based on
theoretical calculations in the absence of LA.28 Although
modest selectivity was observed, a single step preparation of
particular tetrasubstituted ethene 3df was achieved, which was
reported to be a synthetic precursor of a potential squalene
synthetase inhibitor P-362233 (Entry 15). The latest synthesis
of 3df relied on a multistep procedure via the cyanoboration of
alkynes developed by Suginome and Murakami.34
Arylcyanation of Alkenes
The arylcyanation across norbornadiene proceeded in an
exo-cis manner with a range of aryl cyanides to give highly
functionalized norbornenes 4 (Table 4), which may nd
applications as monomers in ring-opening metathesis polymerizations.35 The originally reported reaction conditions for this
particular transformation in the absence of LA catalysts
accommodated a narrow scope of aryl cyanides, primarily
electron-poor ones. The use of 1,2-bis(dimethylphosphino)ethane (DMPE) as a ligand was found to be crucial;
monodentate and other bidentate phosphine ligands were
totally ineective. Notably, no double addition products were
observed. Whereas intermolecular arylcyanation of other
alkenes remains elusive even with the newly developed
nickel/LA cooperative catalysis, the intramolecular addition
across unactivated alkenes proceeds eciently with nickel/
AlMe2Cl catalysis (Table 5). The transformations of aryl
cyanides 5 having double bonds tethered through various
linker moieties proceeded in a 5- or 6-exo-trig manner to give
a variety of nitrile products 6 having cyclic structures and
quaternary carbons at a position to the cyano group.36 We
investigated the stoichiometric reaction of substrate 5a with
[Ni(cod)2], P(n-Bu)3, and AlMe2Cl (Scheme 3). Upon mixing,
the immediate formation of 2-nitrilenickel complex 7 was
Table 4. Arylcyanation of Norbornadiene Catalyzed by
Ni/AlMe2Cl
Ar CN
1 (1.0 mmol)
+

[Ni(cod)2] (1 mol %)
DMPE (1 mol %)
AlMe2Cl (4 mol %)
toluene, 80 C

Ar
NC
4

(1.5 mmol)

Entry
1
2a)
3
4
5

1
1a
1b
1d
1e
1g

a) Reaction run at 100 C.

Time/h
4.5
2
2
10
5.5

Yield
69
57
69
59
58

of 4/%
(4a)
(4b)
(4d)
(4e)
(4g)

Y. Nakao

Bull. Chem. Soc. Jpn. Vol. 85, No. 7 (2012)

5a + [Ni(cod)2] + P(n -Bu)3 + AlMe2Cl

Table 5. Intramolecular Arylcyanation of Alkenes Catalyzed by Ni/AlMe2Cl

R1

CN

[Ni(cod)2] (5 mol %)
PMe3 (10 mol %)
AlMe2Cl (20 mol %)

R4

NC
R2
R1

R3 toluene, 100 C

X
R2
R1,

R2,

R3,

Entry

rt
R3
R4

R4,

Al

X = H, Me, H, H, CH2 (5a)

H, Me, H, H, NMe (5b)
H, Me, H, H, NBn (5c)
Cl, Me, H, H, NBn (5d)
MeO, Me, H, H,NBn (5e)
H, Ph, H, H, NBn (5f)
H, SiMe2Ph, H, H, NBn (5g)
H, Me, Ph, H, NBn (5h)
H, Me, H, Ph, NBn (5i)
H, Me, H, H, (CH2)2 (5k)
H, Me, H, H, BnNCH2 (5l)

Time/h

rt

Ni

Ni

CN
O

C
N
8

7
L = P(n -Bu)3
Al = AlMe2Cl

60 C

Al
ratedetermining

5a
Al
Me

C N

Yield/%
CN

Al
60 C

Ni
10

Product

6a

N
Bn
5j

735

C
Ni
L L
9

Scheme 3. Mechanism of the intramolecular arylcyanation

of alkenes.

1
2a)
3

5a
5b
5c

7
4
7

X = CH2
X = NMe
X = NBn

93 (6a)
86 (6b)
79 (6c)
CN

R
N
Bn

4
5

5d
5e

7
7

R = Cl
R = MeO
R

82 (6d)
85 (6e)
CN

N
Bn

6
7

5f
5g

6
6

R = Ph
R = SiMe2Ph

89 (6f )
84 (6g)

NC

8b)

5h

Ph
H

0.5

88 (6h)c)

N
Bn

NC

9b)

5i

H
Ph

0.5

76 (6i)d)

N
Bn

CN

10e)

5j

74 (6j)

N
Bn
CN

11f )
12

5k
5l

3
3

X = CH2
X = NBn

91 (6k)
96 (6l)

a) Reaction run on a 3.0 mmol-scale. b) PPhMe2 was used as a

ligand. c) dr = 98:2 (>99:1 after isolation). d) dr = 97:3
(>99:1 after isolation). e) PPh3 was used as a ligand. f ) DMPE
was used as a ligand.

noted, which underwent oxidative addition to give nickel(II)

complex 8 after 6 h at room temperature. The structures of both
of the nickel complexes having a cyano group coordinated to

AlMe2Cl were unambiguously conrmed by both NMR

spectroscopy and X-ray crystallography. Accordingly, the
reaction mode by the cooperative action of both the nickel
and aluminum complexes to activate ArCN bonds was
identied experimentally. No 2-arenenickel complexes were
observed, suggesting that the mechanism of ArCN activation
might dier either in the presence or absence of LA catalysts.
Upon heating at 60 C for 46 h, nickel(II) complex 8 was
converted to another 2-nitrilenickel complex 10, possibly via
the migratory insertion of the double bond in 8 to the ArNi
bond to give alkyl(cyano)nickel species 9 and the subsequent
reductive elimination of the C(sp3)CN bond. Treatment of 10
with 5a resulted in the regeneration of 8, thus showing
snapshots of the proposed catalytic cycle. These data also
suggested that the rate-limiting step of this particular intramolecular transformation was either the substitution of the
bound phosphorus with the tethered alkene or the migratory
insertion. With the scope and detailed mechanism of the
intramolecular arylcyanation reaction of alkenes established,
we next studied a synthetically intriguing enantioselective
variant. After extensive screening of known chiral ligands, we
found that i-Pr-Foxap37 showed high enantioselectivity in the
formation of various indolines having a quaternary stereocenter
at the C-3 position in good yields (Table 6).38 In some cases,
related chiral P,N ligand i-Pr-Phox39 showed better enantioselectivity. Optically active indolines thus obtained served as
synthetic precursors for biologically active alkaloids such as
()-esermethole (Scheme 4), which reportedly led to potent
acetylcholinesterase inhibitors such as ()-physostigmine40
and ()-phenserine.41 Likewise, a chiral ligand for the
enantioselective construction of a tetrahydronaphthalene having a benzylic quaternary stereocenter was identied to be
ChiraPhos.42 This allowed for the formal total synthesis of
()-eptazocine,43 an analgesic substance available commercially, by taking advantage of the enantioselective intramolecular arylcyanation of alkenes followed by the subsequent
reduction of the cyano group (Scheme 5). A closely related
enantioselective intramolecular arylcyanation of alkenes focus-

736

Bull. Chem. Soc. Jpn. Vol. 85, No. 7 (2012)

AWARD ACCOUNTS

Table 6. Enantioselective Intramolecular Arylcyanation of

Alkenes Catalyzed by Ni/AlMe2Cl
[Ni(cod)2] (10 mol %)
(S,S )-i -Pr-Foxap (20 mol %)
AlMe2Cl (40 mol %)

CN
N
Me

MeO

DME, 100 C

Entry
1
2
3
4
5
6a)
7

5
5m
5n
5o
5p
5q
5r
5s

N
(S )-i -Pr-Phox

Time/h
40
40
40
160
120
80
40

Yield/%
87 (6m)
87 (6n)
93 (6o)
88 (6p)
46 (6q)
91 (6r)
55 (6s)

Ee/%
93
93
96
95
93
73
97

a) Reaction run with (S)-i-Pr-Phox.

CN

MeO

CN

MeO

5b

O
N
Me
(S )-6b
88%, 96% ee
c

N
Me
40%, 96% ee

MeO
NH
N H
Me
64%, 96% ee

HO

83%, 92% ee

NMe

()-eptazocine

Scheme 5. Formal synthesis of ()-eptazocine via the

enantioselective intramolecular arylcyanation of alkenes.
Reagents and conditions: (a) [Ni(cod)2] (5 mol %), (R,R)ChiraPhos (6 mol %), AlMe2Cl (20 mol %), 120 C, 1 h;
(b) DIBAL-H (2.0 equiv), toluene, 78 C, 2 h, then 1 M
HCl aq., THF, 0 C to rt, 2 h.

PPh2

(S,S )-i -Pr-Foxap

CHO ref 44

N
PPh2

Fe

CN
MeO

(R )-6t
98%, 92% ee

MeO

R = Me (5m); Et (5n); i -Pr (5o); Bn (5p); Me2C=CHCH2 (5q);

CH2OSiMe2t -Bu (5r); Ph (5s)
O

5t

CN

N
Me
6

CN

MeO
NMe
N H
Me
()-esermethole
92%, 96% ee

Scheme 4. Total synthesis of ()-esermethole via the

enantioselective intramolecular arylcyanation of alkenes.
Reagents and conditions: (a) [Ni(cod)2] (10 mol %), (R,R)i-Pr-Foxap (20 mol %), AlMe2Cl (40 mol %), DME, 100
C, 10 h; (b) PhIO (6.0 equiv), CH2Cl2, rt, 2.5 h; (c) LiAlH4
(4.0 equiv), THF, rt, 1 h, then reux, 0.5 h; (d) HCHO aq.
(5.0 equiv), NaBH(OAc)3 (5.0 equiv), MeOH, 0 C to rt,
1.5 h.

ing on substrates having a methylene linker was reported

by Jacobsen and Watson, also with a chiral nickel catalyst
and BPh3 as a LA cocatalyst.44 These enantioselective intramolecular carbocyanation reactions across alkenes, including
the aforementioned intramolecular cyanocarbamoylation of
alkenes catalyzed by palladium,22 can be powerful synthetic
alternatives to the enantioselective intramolecular Heck reactions.45 Whereas a requisite functionality must be preinstalled
onto an olen moiety in the Heck strategy, the carbocyanation
allows the use of simple alkenes because the cyano group is
retained in the resultant cyclization products.

Alkenylcyanation of Alkynes
With the highly eective nickel/LA cooperative catalysis
system in hand, we hoped to expand the scope of the nitriles
in the carbocyanation chemistry as mentioned above. Indeed,
alkenyl cyanides 11, which do not participate in the carbocyanation reaction in the absence of LA cocatalysts, undergo the
transformation by the cooperative catalysis to give variously
substituted 1,3-dienenitriles 12 (Table 7).31 The use of BPh3
as a LA catalyst was crucial to prevent the double bond
isomerization of 12 under the reaction conditions. The reason
that only the starting alkenyl cyanides participated in the
transformation, while the adducts were inert toward further
activation and the possible formation of polymeric products,
Table 7. Alkenylcyanation of Alkynes Catalyzed by Ni/BPh3
R3

R5

[Ni(cod)2] (2 mol %)
R4
CN PMe3 (4 mol %)
R3
11 (1.0 mmol) BPh3 (8 mol %)
+
R4
R1
R2 toluene, 80 C
2 (1.2 mmol)

R5

R5
CN + NC

R1
12

R2

R1

R3
R4

R2
12'

R3, R4, R5 = Ph, H, H (11a)

H, Et, H (11b)
(CH2)5, H (11c)
Ph, Ph, H (11d)
Ph, H, CN (11e)

Entry

11

1
2
3
4
5b)
6
7

11a
11b
11c
11d
11e
11a
11a

2a
2a
2a
2a
2a
2dd)
2gd)

Time/h
20
15
21
46
13
3
15

12
94
78
91
94
81
44
66

Isolated yield/%
12
(12aa)

(12ba)a)

(12ca)

(12da)

(12ea)c)

(12ad)
37 (12ad)
(12ag)e) <5

a) 4Z/4E = 84:16. b) Reaction run with Ni/Ph2P(CH2)4PPh2/

BPh3 = 4/4/16 mol %. c) An isomer was isolated in ca. 2%
yield. d) 2.0 mmol. e) A mixture of isomers was isolated in ca.
7% yield.

Y. Nakao

Bull. Chem. Soc. Jpn. Vol. 85, No. 7 (2012)

Table 8. Alkynylcyanation
Ni/BPh3

of

Alkynes

Catalyzed

by

3
R3
[Ni(cod)2] (1 mol %) R
R3
CN Xantphos (1 mol %)
13 (1.0 mmol) BPh3 (3 mol %)
CN NC
+
+
R1
R2 toluene
R1
R2
R1
R2
2 (1.0 mmol)
PPh2
PPh2
14'
14
O
Xantphos

R3 = t -BuMe2Si (13a)
Et3Si (13b)
t -BuMe2SiC C (13c)
Ph (13d)
cyclohexen-1-yl (13e)
n -Hex (13f)
Cl(CH2)3 (13g)
NC(CH2)3 (13h)
MeCH(OSiMe2t -Bu) (13i)

Entry
1
2
3a)
4b)
5b)
6b)
7b)
8b)
9b)
10
11
12
13
14
15
16
17
18

13
13a
13b
13c
13d
13e
13f
13g
13h
13i
13a
13a
13a
13a
13a
13a
13a
13a
13a

2
Temp/C
2a
80
2a
80
2a
80
2ac)
100
2ac)
80
2ac)
100
2ac)
100
2ac)
100
2ac)
100
2d
80
2h
80
2i
80
2k
40
2l
40
2md)
40
2n
40
2o
40
2p
40

R1, R2 = Me, CH(OEt)2 (2h)

Me, Ph (2i)
4-MeOC6H4 (2j)
H, n -Hex (2k)
H, (CH2)3Cl (2l)
H, (CH2)3CO2Me (2m)
H, (CH2)3CN (2n)
H, cyclohexen-1-yl (2o)
H, 4-NCC 6H4 (2p)

Time/h
21
24
21
3
2
3
3
4
1
49
39
56
15
15
17
15
15
17

Yield/% 14:14
95

95

72

69

67

72

54

35

47

82
22:78
84
13:87
94
60:40
96
83:13
79
82:18
93
87:13
99
88:12
86
95:5
96
>95e):5

a) Reaction run with Ni/Xantphos/BPh3 = 3/3/9 mol %.

b) Reaction run with Ni/Xantphos/BPh3 = 10/10/30 mol %.
c) 2.0 mmol. d) 1.1 mmol. e) E/Z = 2:98.

13a
+
[Ni(cod)2]
+
Xantphos benzene, rt
+
84%
BPh3

t -BuMe2Si

737

N
Ni
O

Ph2P

BPh3

PPh2

15
2a (5.0 equiv)
BPh3 (2.0 equiv)
toluene, 80 C, 14 h

81% (GC)

15 (1 mol %)
t -BuMe2Si
BPh3 (2 mol %)
1a
+
toluene, 80 C, 21 h
2a
(1.0 mmol each)
Pr
94%
14aa

CN
Pr

Scheme 6. Synthesis of trans-(xantphos)Ni(CNBPh3)(CCSiMe2t-Bu) (15) and its stoichiometric and catalytic

reactions.

and BPh3 to give highly functionalized conjugated enyne

products 14 stereo- and regioselectively (Table 8).47 In the
absence of BPh3, the reaction gave poor yields of 14, and the
co-trimerization of both alkyne substrates to form substituted
benzenes was a major reaction pathway. Various functional
groups were tolerated under the reaction conditions: the
exclusive activation of C(sp)CN bonds over C(sp2)CN and
C(sp3)CN bonds highlights this aspect (Entries 8, 16, and 18).
The stoichiometric reaction of 13a with [Ni(cod)2], Xantphos,
and BPh3 allowed us to identify trans-nickel(II) complex 15
in 84% yield, and obtain unambiguous structural conrmation
by NMR spectroscopy and X-ray crystallography (Scheme 6).
Treatment of 15 with 5.0 molar equivalents of 2a in the
presence of added BPh3 gave 14aa in 81% yield as estimated
by GC. Alternatively, 15 served as a catalyst for the reaction
of 13a with 2a to give 14aa in 94% isolated yield, showing
that 15 was likely an intermediate in the catalytic cycle of the
reaction.
Alkynylcyanation of 1,2-Dienes and Norbornadiene

should be the dierent number of substituents attached to the

double bond of the alkenyl cyanides: adducts 12 always
possess a substituent at the -position, which should sterically
retard further activation of their CCN bonds, whereas substrates 11 have no -substituents. Indeed, the reactions of alkyl-substituted alkenyl cyanides were sluggish. Nevertheless,
the -cyano-substituent of benzylidenemalononitrile 11e did
not aect the reaction, and the CCN bond trans to the
-phenyl substituent was exclusively activated to give 1,3dicyano-substituted 1,3-diene product 12ea stereoselectively
(Entry 5).
Alkynylcyanation of Alkynes
Alkynyl cyanides 13 participated in the carbocyanation reaction with the cooperative catalyst derived from [Ni(cod)2], 4,5bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos),46

Under the conditions of the alkynealkynylcyanation reaction, 1,2-dienes 16 also underwent the addition of the alkynyl
and cyano groups of 13a exclusively across their internal
double bond, to give another type of conjugated enyne product 17 regioselectively (Table 9). A possible catalytic cycle
for the reaction should also involve 15 as an intermediate,
which undergoes the coordination and the subsequent migratory insertion of the 1,2-diene into the alkynylNi bond
to give a -allylnickel intermediate (Scheme 7). Reductive
elimination closes the catalytic cycle to generate functionalized enyne 17. The origin of the reverse regioselectivity
with silylallene 16e is yet to be understood (Entry 5). While
the alkynylcyanations of 1,3-dienes and simple alkenes are
elusive, norbornadiene undergoes the transformation, again
in an exo-cis fashion, to give functionalized norbornene 18
(eq 10).

738

Bull. Chem. Soc. Jpn. Vol. 85, No. 7 (2012)

AWARD ACCOUNTS

Table 9. Alkynylcyanation of 1,2-Diene Catalyzed by

Ni/BPh3
[Ni(cod)2] (2 mol %)
Xantphos (2 mol %) Si
13a (0.80 mmol) BPh3 (6 mol %)
+

toluene, 50 C
R
16 (0.80 mmol) Si = SiMe2t -Bu

Table 10. Cyanoesterication of Alkynes Catalyzed by

Ni/BAr3
Si

CN + NC
17

17'

R = n -Hex (16a); (CH2)2Ph (16b); (CH2)2OSiMe2t-Bu (16c);

Cy (16d); SiMe2n -Bu (16e)

Entry
1
2
3
4
5

Time/h
19
24
17
59
66

16
16a
16b
16c
16d
16e

Yield/%
73
82
75
74
55

17:17
93:7
91:9
92:8
>95:5
5:>95

Si
17
P
13a

Ni

C
N
B

P
P

Ni

Si
Si

Ni
P
C
N
B

P
R

NC

R2

OEt

R1

R2
19'

R1, R2 = n -Hex, SiMe3 (2q)

geranylCH2, SiMe3 (2r)
MeO2C(CH2)3, SiMe3 (2s)
t -BuMe2SiO(CH2)3, SiMe3 (2t)
PhthN(CH2)3, SiMe3 (2u)

Entry
1
2
3
4
5
6
7
8

2
2a
2c
2e
2q
2r
2s
2t
2u

Cond.a)
A
A
A
B
B
B
B
B

Time/h
18
21
46
22
22
41
46
51

Yield/%
80
75
49
75
64
62
67
67

19:19

>95:5
5:>95
5:>95
5:>95
5:>95
5:>95

16

= Xantphos

P
B = BPh3
Si = SiMe2t -Bu

O
CN

15

[Ni(cod)2] (5 mol %)
CN PAr13 (20 mol %)
EtO
O
(1.0 mmol) BAr23 (20 mol %)
EtO
+
R1
R2 solvent, 35 C
R1
2 (1.0 mmol)
19
1
Ar = 3,5-(CF3)2C6H3
Ar2 = Ph or C6F5

a) Conditions A: B(C6F5)3/toluene; B: BPh3/1,4-dioxane.

Si
R

Ni
P
C

Si
R
P
P

N
B

Ni
C
N
B

Scheme 7. A plausible mechanism for the alkynylcyanation

of 1,2-dienes.

[Ni(cod)2] (2 mol %)
Xantphos (2 mol %)
13a (1.0 mmol) AlMe2Cl (4 mol %)
t -BuMe2Si
+
NC
toluene, 80 C, 17 h
18, 89%

10

(1.0 mmol)

Cyanoesterification of Alkynes
The cleavage of the CCN bond of cyanoformates and the
addition of both alkoxycarbonyl and cyano groups across
unsaturated bonds should give access to highly functionalized
products. The double functionalization reactions were originally achieved across 1,2-dienes by nickel catalysis,27 and

across norbornene and norbornadiene by palladium catalysis.20

Although the cyanoesterication of alkynes has recently been
achieved in an intramolecular manner by palladium catalysis,21
the intermolecular reactions have been developed in the
authors laboratory using the nickel/Lewis acid catalyst.48
Thus, the addition of ethyl cyanoformate across 2a proceeded
stereoselectively in the presence of catalytic amounts of
[Ni(cod)2], [3,5-(CF3)2C6H3]3P, and B(C6F5)3 at 35 C to give
-cyano-substituted ,-unsaturated ester 19aa in 80% yield
(Table 10, Entry 1). The identical reaction in the absence
of B(C6F5)3 gave only a 4% yield of 19aa even at 100 C.
The cyanoesterication proceeds across a variety of alkynes
with excellent stereo- and regioselectivities (Table 10). In
contrast, the addition of thiocyanoformates was accompanied
by decarbonylation to give a thiocyanation product in the
presence of a similar set of catalysts (eq 11). This particular
transformation was found to be catalyzed more eectively by
palladium, whereas the thiocyanation of terminal alkynes was
previously reported by Ogawa and co-workers by directly using
phenyl thiocyanate and a palladium catalyst.49
O
cat. M (5 mol %)
CN P(4-CF3C6H4)3 (10 mol %)
PentS
(1.0 mmol)
B(C6F5)3 (20 mol %)
PentS
CN
+
11
2a (1.0 mmol) toluene, 100 C, 24 h
Pr
Pr
M = [Ni(cod)2]: 68%
[CpPd(allyl)]: >95%

Cyanocarbamoylation of Alkynes
Similarly, cyanoformamides 20 underwent the addition
across alkynes to give -cyano-substituted ,-unsaturated
amides 21 stereo- and regioselectively (Table 11). The stoi-

Y. Nakao

Bull. Chem. Soc. Jpn. Vol. 85, No. 7 (2012)

Table 11. Cyanocarbamoylation of Alkynes Catalyzed by

Ni/BPh3

Table 12. Allylcyanation

Ni/AlMe2Cl

Alkynes

Catalyzed

by

R5

O
R3

N
CN
R4
20 (1.0 mmol)
+
R1
R2
2 (1.0 mmol)

[Ni(cod)2] (5 mol %)
PPh2R5 (10 mol %)
BPh3 (15 mol %)
solvent, 80 C

20
20a
20b
20c
20a
20a
20a
20a
20a

R3

R3

N
R4

CN
R2

2
2a
2a
2a
2d
2q
2r
2t
2u

R1

21

R5 = Cy or i -Pr
R3
N
R4

R3, R4 = Me (20a)
Me, Bn (20b)
(CH2)2O(CH2)2 (20c)

Entry
1
2
3
4
5
6
7
8

of

739

O
CN

R1
R2
not observed

Cond.a)
A
A
A
A
B
B
B
B

Time/h
17
27
23
24
22
41
39
50

Yield/%
92
82
87
31
66
56
66
42

a) Conditions A: PPh2Cy/toluene; B: PPh2i-Pr/1,4-dioxane.

20a
+
[Ni(cod)2]
+
2 PPh2Cy
+
BPh3

CN
R4
23 (1.0 mmol)
+
R1
R2
2 (1.0 mmol)

[Ni(cod)2] (2 mol %)
P(4-CF3C6H4)3 (4 mol %)
AlMe2Cl (6 mol %)

R5
R3
CN

toluene, 50 C

R4
R1
24

R2
R5

R3, R4, R5 = H (23a)

Ph, H, H (23b)
(CH2)3, H (23c)
Me, H, Me (23d)

R3
NC
R4
R2
24'
rarely observed

R1

Entry
1
2
3
4a)
5
6
7
8

23
23a
23b
23c
23d
23a
23a
23a
23a

2
2a
2a
2a
2a
2i
2k
2l
2n

Time/h
24
72
48
24
24
4
4
4

Yield/%
96
74
82
61
64
67
60
46

24:24

92:8
>95:5
>95:5
>95:5

a) Reaction run with Ni/Ligand/AlMe2Cl = 20/40/60 mol %.

O
benzene, rt

Me2N

PPh2Cy
Ni C N BPh3
PPh2Cy
22

2a (5.0 equiv)
benzene, 60 C, 1 h
22 (5 mol %)
BPh3 (10 mol %)
20a
+
toluene, 80 C, 17 h
2a
(1.0 mmol each)

40% (GC)

O
Me2N

CN
Pr
21aa

Pr

Scheme 8. Synthesis of trans-(CyPh2P)2Ni(CNBPh3)(CONMe2) (22) and its stoichiometric reaction with 2a.

chiometric reaction of 20a, [Ni(cod)2], PPh2Cy, and BPh3 gave

nickel(II) complex 22, which was unambiguously identied
by both NMR spectroscopy and X-ray crystallography
(Scheme 8). Of particular note is the coordination of the cyano
group to BPh3 even in the presence of the Lewis basic
aminocarbonyl moiety. Oxidative adduct 22 reacted with
2a to give 21aa, suggesting its intermediacy in the catalytic
cycle of the cyanocarbamoylation reaction. The origin of the
regioselectivity with sterically biased alkynes that favors the
formation of 19 (cyanoesterication) and 21 (cyanocarbamoylation) remains elusive, whereas interaction of the carbonyl
functionalities with the silyl group and/or an alternative
cyanonickelation pathway could be operative in the reversal
of the regioselectivity.

Allylcyanation of Alkynes
Although the allylcyanation of alkynes could be catalyzed
by a nickel catalyst alone (eq 8), the presence of a LA
cocatalyst allowed the carbocyanation to proceed with reduced
nickel catalyst loading at a lower reaction temperature
(Table 12).50 Owing to the milder reaction conditions, excellent
stereo- and regioselectivities were achieved to give disubstituted acrylonitriles 24 with a variety of functional groups,
starting from a range of allyl cyanides 23 and alkynes. The
synthetic utility of the methodology for the synthesis of
trisubstituted ethenes was highlighted by the total synthesis
of plaunotol, an antibacterial natural product active against
Helicobacter pylori (Scheme 9). Thus, the trisubstituted C6
C7 double bond of the target natural product was successfully
constructed by the stereo- and regioselective allylcyanation of
alkyne 2v with -siloxyallyl cyanide 23e. The CC bond
formation at the -position of the cyano group of 23e suggested
the intermediacy of a -allylnickel intermediate.
Alkylcyanation of Alkynes
The CCN bond of acetonitrile (25a) was eciently
activated by nickel/LA cooperative catalysis to achieve the
methylcyanation of alkynes (Table 13), whereas the alkyl cyanide substrate was completely inert under the reaction conditions in the absence of LA cocatalysts. Particularly eective as
LA catalysts were AlMe3 and AlMe2Cl, whose methyl groups
were found irrelevant to those in the methylcyanation products
26 as evidenced by complete incorporation of the CD3 group
from acetonitrile-d3 (eq 12). Although the excellent regioselectivity of the addition reaction was established, partial

740

Bull. Chem. Soc. Jpn. Vol. 85, No. 7 (2012)

AWARD ACCOUNTS

OSiMe3
NC
23e (40 mmol)
+

a
64%

[Ni(cod)2] (5 mol %)
D3C CN
PPh2t -Bu (10 mol %)
(1.0 mmol)
AlMe3 (20 mol %)
+
2a (1.0 mmol) toluene, 80 C, 5 h

CN

24ev
regioselectivity = 96:4

2v (40 mmol)
b

Et CN
25b (1.0 mmol)
+
2a (2.0 mmol)

CN

61%

93%

D3C

CN

12

Pr
Pr
66%, 99%D

[Ni(cod)2] (10 mol %)

SPhos (20 mol %)
AlMe3 (40 mol %)
toluene, 50 C, 8 h

OMe

CHO

Et

93%

Pr

Pr CN
25c (1.0 mmol)
+
2a (2.0 mmol)

59%

Me

e, quant

RO
Zr

HO
R = Sii -Pr3
R = H: Plaunotol

g, 89%

Cl
Cl

Zr catalyst

Scheme 9. Total synthesis of plaunotol via allylcyanation.

Reagents and conditions: (a) [Ni(cod)2] (2 mol %), P(4CF3C6H4)3 (4 mol %), AlMe3 (8 mol %), toluene, 35 C,
8 h, then 1 M HCl aq., THF, 0 C to rt; (b) AcC(N2)P(O)(OMe)2, K2CO3, MeOH, 0 C to rt, 24 h; (c) DIBAL-H,
toluene, 78 C, 1.5 h, then SiO2; (d) LiAlH4, THF, 0 C to
rt, 20 min; (e) TIPS-Cl, imidazole, DMF, rt, 3 h; (f ) AlMe3,
Zr catalyst (5 mol %), MAO (5 mol %), rt, 48 h, then
n-BuLi, (HCHO)n, THF, rt, 1.5 h; (g) TBAF, THF, rt, 12 h.
Table 13. Methylcyanation of Alkynes Catalyzed by Ni/LA
[Ni(cod)2] (5 mol %)
Me CN
ligand (10 mol %)
25a (1.0 mmol) LA (20 mol %)
Me
R2
CN Me
+
+
R1
R2 toluene, 80 C
R1
R2
R1
CN
2 (1.0 mmol)
26
26'
R1, R2 = Et, Ph (2w)

Entry
1b)
2
3c)
4
5
6
7

2
2a
2c
2w
2q
2r
2s
2t

Cond.a)
A
A
B
C
C
C
C

Time/h
4
10
23
12
24
21
24

Yield/%
71
91
49
74
63
38
60

Pr

13

Pr
Pr
27, 1%

78%

SPhos

R=H
R = Sii -Pr3

CN

+
MeO PCy2

RO

CN

26/26
>95:5
88:12
61:39
91:9
86:14
91:9
75:25

a) Conditions A: PPh2t-Bu/AlMe3; B: PPh3/AlMe3;

PPh2t-Bu/AlMe3 with 10 mol % [Ni(cod)2]. b) Reaction run
on a 10.0 mmol scale. c) Reaction run using 25a as a solvent.

isomerization of the initial cis-adducts was observed to give

stereoisomeric mixtures of the methylcyanation products. The
use of the biarylphosphine ligands developed by Buchwald51

[Ni(cod)2] (10 mol %)

SPhos (20 mol %)
AlMe3 (40 mol %)
toluene, 50 C, 30 h
Pr

Pr

CN

Pr

+
+
27
H
Pr (19% by GC)
10%

Pr
CN 14
Pr
15%

Pr

was found to be eective for the ethylcyanation of alkynes

using propionitrile (25b) (eq 13). A small amount of hydrocyanation product 27 was observed, derived from the -hydride
elimination of an ethylnickel intermediate generated upon the
oxidative addition of propionitrile to nickel(0). This unwanted
reaction pathway competed with the carbocyanation reaction
when nitriles having higher alkyl chains, such as butyronitrile
25c, were used (eq 14). Alkyl cyanides having no -hydrogen,
however, eciently reacted with alkynes under nickel/LA
catalysis. Arylacetonitriles added across a range of alkynes to
give the corresponding alkylcyanation products in good yields
(Table 14).52 Heteroaryl moieties, even with unprotected NH,
were also tolerated under the reaction conditions (Entries 6 and
7). Terminal alkynes also participated in the alkylcyanation
reaction, although the origin for the reversed regioselectivity
remained elusive (Entries 1315). Other substituted acetonitriles, including phthalimidyl, THP-protected hydroxymethyl, and trimethylsilyl ones, participated in the carbocyanation
reaction (eqs 1517). The addition of (S)--phenylpropionitrile
25n of 85% ee with 2a was investigated to gain mechanistic
insights into the alkylcyanation reaction (eq 18). The corresponding adduct (S)-26na of 41% ee was obtained in 22%
yield, and its absolute conguration was determined based on
the reported optical rotation of (R)-2-phenyl-3-hexanone53 after
oxidative cleavage of the double bond in (S)-26na. Also
obtained were hydrocyanation product 27, styrene, and hydrocinnamonitrile in 35%, 44%, and 3% yields, respectively,
as estimated by GC. Recovered (S)-25n indicated 80% ee,
suggesting that background racemization under these conditions was likely slower than the racemization during the
carbocyanation process. No further racemization of (S)-25n
was noted under the present reaction conditions. These results
suggested the oxidative addition of a CCN bond of alkyl

Y. Nakao

Bull. Chem. Soc. Jpn. Vol. 85, No. 7 (2012)

Table 14. Alkylcyanation of Alkynes Using Arylacetonitriles Catalyzed by Ni/AlMe2Cl

[Ni(cod)2] (2 mol %)
Ar1
CN PAr2Cy2 (4 mol %)
25 (1.0 mmol) AlMe2Cl (8 mol %)
+
R1
R2 toluene
2 (1.0 mmol)
Ar2 = 2-mesityl
Ar1 = Ph (25d)
4-MeOC6H4 (25e)
4-ClC6H4 (25f)
2-MeO2CC6H4 (25g)
3-thienyl (25h)
2-pyrrolyl (25i)
3-indolyl (25j)

Entry

25

1
2
3
4
5
6a)
7a)
8
9
10
11
12a)
13c)
14c)
15c)

25d
25e
25f
25g
25h
25i
25j
25d
25d
25d
25d
25d
25d
25d
25d

2a
2a
2a
2a
2a
2a
2a
2c
2x
2i
2e
2g
2kd)
2yd)
2zd)

Ar1

CN

Ar1

NC
+

R1
26

R2

R1

Me3Si

CN

Pr
89%
[Ni(cod)2] (20 mol %)
XPhos (40 mol %)
AlMe2Cl (20 mol %)

R2
26'

+
2a
Ph
CN
(5.0 equiv)
(S )-25n, 85% ee

R1, R2 = Ph (2x)
H, Cy (2y)
H, t -Bu (2z)

Temp
/C
35
35
80
80
80
35
35
80
80
35
35
35
35
35
35

[Ni(cod)2] (5 mol %)
CN PCyp3 (10 mol %)
Me3Si
25m (1.0 mmol) BPh3 (20 mol %)
+
2a (1.5 mmol) toluene, 80 C, 13 h

741

17

Pr

toluene, 80 C, 0.5 h
83% conv. of 25n

Ph

Time
/h
8
8
18
5
2
10
48
70
73
24
21
53
11
9
9

Yield
/%
90
93
74
56
95
54
69
93
86
85
94
56
48
61
54

Pr

26:26

b)
92:8
>95:5
81:19
12:88
8:92
5:>95

a) Reaction run with Ni/PAr2Cy2/AlMe2Cl = 10/20/40

mol %. b) E/Z = 79:21 (82:18 at 1.5 h). c) Reaction run with
Ni/PPh2Me/AlMe2Cl = 10/20/40 mol %. d) 3.0 mmol.

CN

CN

CN

+
Pr

Pr

Ph

Pr

Ph

44% (GC)

27
35% (GC)

(S )-26na
22%, 41% ee

18

+
3% (GC)

i -Pr
i -Pr
i -Pr PCy2
XPhos

R4
L

R3

L
Ni

R1

R3
R1

C
R2

N
LA

LA

R4

R2
R1

Ni

R3

Ni

R4L

L
R4

R3 = Ar, PhthN, THPO, SiMe3

R4 = H, Me
L = phosphine

R2

LA

R3

CN

O
N

R1

CN

O
25k (1.0 mmol)
+
2a (2.0 mmol)

[Ni(cod)2] (5 mol %)
PAr3 (10 mol %)
BPh3 (20 mol %)

toluene, 80 C, 30 h

LA

R4

O
CN 15

Pr
O Pr
64%
+
isomeric mixture
of 1:2 adducts
(1020%)

R2

N
C

R3
L

Ar = 3,5-Me2 4-MeO C6H2

R3

retention of
stereochemistry

Ni

R4

R4
N

C
L

Ni

R3 = Ph; R4 = Me
LA
N styrene 2a
C
Ph

Ni
H

CN
R1

LA

Pr
Pr

LA

R3

N
C
Ni

+L

styrene 2a

[Ni(cod)2] (10 mol %)

CN P(p -An)3 (20 mol %)
O
O
25l (1.0 mmol) BPh3 (40 mol %)
+
2a (1.5 mmol) toluene, 80 C, 3 h

O
O

CN

16

cyanides with retention of conguration, in contrast to the

nonstereospecic oxidative addition of benzyl halides to
nickel(0).54 The oxidative addition of acetonitrile to nickel(0)

LA

Pr

Pr

N
C

Pr
Pr
82%
+
isomeric mixture
of 1:2 adducts
(1020%)

+L

LA
N

Ph

Ni
L

Ni
L

27 + L2Ni0 + LA

Ph(CH2)2CN
+ L2Ni0 + LA

pathways for by-product formation in Eq. 18

Scheme 10. A plausible mechanism for the alkylcyanation

of alkynes.

R2

742

Bull. Chem. Soc. Jpn. Vol. 85, No. 7 (2012)

AWARD ACCOUNTS

Table 15. Alkylcyanation of Alkynes Using -HeteroatomSubstituted Alkanenitriles Catalyzed by Ni/AlMe3

R3
[Ni(cod)2] (10 mol %)
P(o -An)3 (10 mol %)
AlMe3 (40 mol %)

X
CN
28 (1.0 mmol)
+
R1
R2
2 (2.0 mmol)

Y
CN
28f

CN

toluene

X, R3 = BnMeN, H (28a)
pyrrolidin-1-yl, H (28b)
pyrrolidin-1-yl, Et (28c)
pyrrolidin-1-yl, Ph (28d)
pyrrolidin-1-yl, OSiMe2t -Bu (28e)
BnO, H (28j)
t -BuMe2SiO, H (28k)
BnS, H (28n)
BnN

R3

CN

R1
29
+
R3

R2

NC
R1

R2
29'

BnN

CN
X
X, Y = NMe, CH2 (28g)
O, CH2 (28l)
O (28m)

CN
28h

28i

Entry
1a)
2c)
3
4
5
6a)
7a)
8
9a)
10
11
12a)
13
14e)
15f )
16c)
17
18c)
19g)

28
28a
28b
28c
28d
28e
28f
28g
28h
28i
28j
28k
28l
28m
28n
28a
28b
28d
28b
28b

2
Temp/C
b)
2a
80
2ab)
80
2a
60
2a
60
2a
60
2ab)
80
2ab)
80
2a
60
2ad)
50
2a
50
2a
50
2a
50
2a
50
2ab)
50
2b
50
2cb)
80
2d
60
2eb)
80
2zb)
50

Time/h
20
9
8
31
3
3
9
111
4
20
40
40
22
24
10
5
14
13
26

Yield/%
88
88
89
90
90
79
82
49
94
64
65
47
66
79
72
94
87
88
74

29:29

91:9
>95:5
>95:5

a) Reaction run with Ni/P(o-An)3/AlMe3 = 5/5/20 mol %.

b) 1.4 mmol. c) Reaction run with Ni/P(o-An)3/AlMe3 =
3/3/12 mol %. d) 1.1 mmol. e) Reaction run with Ni/P(t-Bu)3/
AlMe3 = 5/5/20 mol % as a ligand. f ) Reaction run with 60
mol % AlMe3. g) Reaction run with Ni/AsPh3/B(C6F5)3 =
3/3/12 mol %.

with retention of conguration was also suggested by theoretical calculations.6o Coordination and then migratory insertion
of alkynes into the ArC(R)HNi bond are followed by
reductive elimination to give rise to the alkylcyanation products
(Scheme 10).55 The absolute conguration can be retained
during the catalytic cycle. The observed partial loss of % ee,
nevertheless, can be ascribed to the -hydride elimination from
the alkylnickel intermediate followed by the reinsertion of
the coordinated olen and/or the reversible exchange of the

olen ligand by alkynes. The formation of the aforementioned

side products supported the occurrence of these possible side
reactions. The competitive -hydride elimination from the
alkylnickel intermediates in the alkylcyanation can be partially
suppressed by introducing a coordinating functionality at the
-position of the cyano group in the alkyl cyanide substrates
(Table 15).56 The intramolecular coordination of heteroatom
functionalities such as nitrogen, oxygen, and sulfur should
occupy the vacant coordination site requisite for the unwanted
-hydride elimination. It is worth noting, nevertheless, that
such substrate design allowed the addition of even secondary
alkyl cyanides across alkynes (Entries 35). The location of the
amino-substituents aects the reaction course: an amino group
at the -position of alkylnitriles retarded the reaction, whereas
its location at the - or -position directed the CC bond
formation at the -position of the amino group, possibly
through ve-membered aza-nickelacycle intermediates generated through the oxidative addition of the CCN bonds
followed by the -hydride elimination and the subsequent
reinsertion of the coordinating double bonds (eqs 19 and 20).57
N
CN
28o (1.0 mmol)
+
2a (2.0 mmol)

[Ni(cod)2] (10 mol %)

SPhos (20 mol %)
AlMe3 (40 mol %)

N
CN

toluene, 50 C, 11 h
77%

Pr

19

Pr

CN [Ni(cod) ] (10 mol %)

2
SPhos (20 mol %)
28p (1.0 mmol)
AlMe3 (60 mol %)
+
toluene, 80 C, 45 h
2a (2.0 mmol)

N
CN

20

45% Pr
Pr
+ 27 (9% by GC)

Summary
In conclusion, we have achieved the carbocyanation reaction
of alkynes with a diverse range of nitriles. In addition to the
reactions across alkynes, the carbocyanation reactions of other
unsaturated compounds, such as norbornadiene and 1,2-dienes,
with some nitriles were also eected. The intramolecular
arylcyanation of alkenes has been developed to allow access
to nitriles having benzylic quaternary stereocenters with high
enantioselectivities. All the developments rely wholly on the
invention of the nickel/LA cooperative catalyst systems, which
signicantly promote the oxidative addition of unreactive
CCN bonds to nickel(0), whereas the reductive elimination of
CCN can also be promoted by LA through the coordination
of a cyano group to the LA.58 We have also discerned the
mechanism of CCN activation by the cooperative catalysis, by
characterizing some nitrilenickel complexes in which cyano
groups coordinate to the LA additives. Nevertheless, to
advance carbocyanation reactions as fully general methods
for CC bond formation, several issues remain to be solved: 1)
the limited scope of alkyl cyanides, and 2) the general intermolecular carbocyanation reactions of alkenes, both of which
should rely on a catalyst design to promote the reductive
elimination of C(sp3)CN bonds over competitive -hydride
elimination. Another issue is the rather limited scope of alkynes
excluding terminal ones, which often suered from competitive
alkyne trimerization and/or oligomerization, particularly in

Y. Nakao

the presence of nickel catalysts coordinated by electrondonating phosphine ligands. These goals will be pursued in
our laboratories to establish the carbocyanation protocol as a
highly general and practical synthetic tool for chemists.
The author is grateful to Profs. Tamejiro Hiyama, Sensuke
Ogoshi, Masaki Shimizu, and Masato Ohashi for their kind
support and fruitful discussions. The author also acknowledges
Profs. Timothy F. Jamison and William D. Jones for stimulating discussions regarding the reaction mechanisms. I appreciate
experimental and intellectual contributions by my co-workers,
Dr. Yasuhiro Hirata, Dr. Akira Yada, Dr. Jen-Chieh Hsieh, Mr.
Shinichi Oda, Mr. Jun Satoh, Mr. Tomoya Yukawa, Mr. Shiro
Ebata, Mr. Masaaki Tanaka, Mr. Hiroaki Idei, Mr. Yuuya
Yamada, and Mr. Eiji Morita. This work has been supported
nancially by a Grant-in-Aid for Creative Scientic Research
(No. 16GS0209), Scientic Research (S) (No. 21225005),
Young Scientists (Nos. 19750076 and 21685023), Priority
Areas Chemistry of Concerto Catalysis (Nos. 19028030
and 20037035) and Molecular Theory for Real Systems
(Nos. 19029024 and 20038027), and Scientic Research
on Innovative Areas Molecular Activation Directed toward
Straightforward Synthesis (No. 22105003) by MEXT and
JSPS. The author also acknowledges Mitsubishi Chemical
Corporation Fund, Japan Chemical Innovation Institute, Showa
Shell Sekiyu Foundation for Promotion of Environmental
Research, The Sumitomo Foundation, The Uehara Memorial
Foundation, General Sekiyu Research & Development Encouragement & Assistance Foundation, Kurata Memorial Hitachi
Science and Technology Foundation, and Takeda Science
Foundation for support.
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Yoshiaki Nakao (born in 1976) was educated in chemistry at Kyoto University (Ph.D. with Profs.
Tamejiro Hiyama and Eiji Shirakawa), Yale University (visiting student with Prof. John F.
Hartwig), and Max-Planck-Institut fr Kohlenforschung (visiting scholar with Prof. Manfred T.
Reetz). Since 2002, he has been an assistant professor at Kyoto University. He received Mitsui
Chemicals Catalysis Science Award of Encouragement (2009), The Society of Silicon Chemistry
Award of Encouragement (2009), Thieme Journal Award (2010), MerckBanyu Lectureship
Award (2010), The Chemical Society of Japan Award for Young Chemists (2010), and The
Commendation for Science and Technology by MEXT, The Young Scientists Prize (2011). His
research interest includes development of new synthetic reactions by metal catalysis for selective
synthesis.