Documenti di Didattica
Documenti di Professioni
Documenti di Cultura
731
Award Accounts
The Chemical Society of Japan Award for Young Chemists for 2010
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
C + R
metal
catalyst
732
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
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
EtO
+
toluene, 110 C, 3 h
EtO
3
NC
78%
Ph
Ph
CN
O
CN
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
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
Pr
toluene, 100 C, 30 h
Pr
CN
Pr
81%
CN
+
+
Pr
CN
Pr
O
EtO
CN
O NC
81%
Pr
Pr
78%
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
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
734
AWARD ACCOUNTS
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
BEt3
9
<1
6
<1
1
1
a) p-An: 4-MeOC6H4.
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)
[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
Time/h
4.5
2
2
10
5.5
Yield
69
57
69
59
58
of 4/%
(4a)
(4b)
(4d)
(4e)
(4g)
Y. Nakao
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
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
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)
736
AWARD ACCOUNTS
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
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
PPh2
CHO ref 44
N
PPh2
Fe
CN
MeO
(R )-6t
98%, 92% ee
MeO
5t
CN
N
Me
6
CN
MeO
NMe
N H
Me
()-esermethole
92%, 96% ee
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'
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
Y. Nakao
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
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
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
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
AWARD ACCOUNTS
toluene, 50 C
R
16 (0.80 mmol) Si = SiMe2t -Bu
CN + NC
17
17'
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'
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
Si
R
Ni
P
C
Si
R
P
P
N
B
Ni
C
N
B
[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
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
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
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
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
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.
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
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
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
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
Pr
CN
Pr
+
+
27
H
Pr (19% by GC)
10%
Pr
CN 14
Pr
15%
Pr
Y. Nakao
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
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
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
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
O
O
CN
16
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
R2
742
AWARD ACCOUNTS
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
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
N
CN
toluene, 50 C, 11 h
77%
Pr
19
Pr
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.
References
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743
744
AWARD ACCOUNTS
Y. Nakao
745
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.