Catalytic conjugate addition of cyanide to enones: Cooperative catalysis of Ni(0) and Gd(OTf)

Article abstract of DOI:10.1055/s-2008-1078264

An efficient, synthetically useful catalytic cunjugate addition of cyanide to enones was developed using cooperative catalysis of Ni(0) and Gd(OTf) ₃. The co-catalyst, Gd(OTf)₃, dramatically accelerated the reaction. The substrate sc

Full text of DOI:10.1055/s-2008-1078264

LETTER
2295
Catalytic Conjugate Addition of Cyanide to Enones: Cooperative Catalysis of
Ni(0) and Gd(OTf)3
Conjugate
A
dditio
u
n
of Cyanide
t
to Eno
a
nes Tanaka, Motomu Kanai,* Masakatsu Shibasaki*
Graduate School of Pharmaceutical Sciences, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
Fax +81(3)56845206; E-mail: mshibasa@mol.f.u-tokyo.ac.jp
Received 5 June 2008
Table 1 Optimization of the Reaction Conditions: Effects of
Abstract: An efficient, synthetically useful catalytic cunjugate ad-
Ligands
dition of cyanide to enones was developed using cooperative catal-
O
OTMS
ysis of Ni(0) and Gd(OTf)3. The co-catalyst, Gd(OTf)3,
dramatically accelerated the reaction. The substrate scope is broad,
including cyclic, linear, branched, and aromatic enones. Synthetic
efficiency of the key conversion in our Tamiflu synthesis, conjugate
cyanation of an enone, was significantly improved by using this
new method. Gadolinium triflate is supposed to facilitate the oxida-
tive addition of Ni(0) to enones, which constitutes a key step in the
catalytic cycle.
Ni(cod)2−ligand
TMSCN (3 equiv)
NHBoc
NHBoc
NHBoc
NHBoc
THF, 70 °C
NC
1s
3s
Entry Ni (mol%) Ligand (mol%)
Time (h) Yield (%)
1
2
3
20
10
10
–
11
24
8
80
Key words: cooperative catalysis, conjugate addition, cyanide,
nickel, gadolinium
cyclooctadiene (10)
norbornadiene (30)
>95
>95
The conjugate addition of cyanide to enones is a useful re-
action in organic synthesis. The control of regioselectivity
(1,4-addition vs. 1,2-addition) in this reaction is a major
concern. After Nagata’s pioneering work using Et2AlCN
as a nucleophile,1 several hard-metal-mediated reactions
were reported.2–4 In our synthesis of Tamiflu (4),5 an im-
portant anti-influenza drug, however, we utilized an en-
tirely distinct method for introducing cyanide to enones
(such as 1r and 1s): Ni(0)–cyclooctadiene (cod) complex
catalyzed conjugate cyanation using TMSCN as a nucleo-
phile. Whereas the hard-metal-mediated conditions were
not effective (no reaction) for conjugate cyanation of
enones, such as 1r and 1s containing multiple Lewis basic
sites, the Ni-catalyzed reaction proceeded in high yield
under mild conditions. This method was rather primitive,
however, with regard to the following points: (1) high cat-
alyst loading (10–50 mol%), and (2) prolonged reaction
time (3–65 h).5 Moreover, substrate generality of this
method has yet to be determined. In this communication,
we report that the catalyst activity improved dramatically
in the presence of a Gd(OTf)3 co-catalyst, leading to a
highly general and synthetically useful catalytic conjugate
addition of cyanide to enones.
longed reaction time with producing insoluble and inac-
tive Ni powder. Thus, additive ligand effects were next
studied to stabilize the catalyst. In the presence of addi-
tional cod (10 mol%), the reaction completed in 24 hours
even using 10 mol% of Ni(cod)2 (entry 2). Further studies
revealed that norbornadiene (nbd) was the optimal ligand,
and the reaction was complete in 8 hours (entry 3). When
phosphine ligands were used instead of diene ligands,
however, the reaction was very sluggish.
We then applied the preliminarily optimized conditions to
a more challenging substrate, 3-methyl-2-cyclohexen-1-
one (1e). The reaction, however, did not proceed at all at
room temperature (Table 2, entry 1). To facilitate the re-
action, the effects of additives were studied. The presence
of a catalytic amount (10 mol%) of Lewis acids, especial-
ly rare-earth-metal triflates, dramatically accelerated the
reaction (Table 2, entries 2–6).6 Specifically, Gd(OTf)3
gave the best result (94% yield, entry 5). TBSCN can be
also used as the nucleophile (entry 7), giving the product
in comparable yield to TMSCN.7 Catalyst loading could
be reduced to 5 mol% without a significant loss of reac-
tion efficiency (entry 8). Gadolinium triflate itself did not
catalyze the reaction in the absence of the Ni catalyst (en-
try 9: no reaction). Therefore, the dramatic acceleration
observed in the presence of Gd(OTf)3 was due to the co-
operative catalysis of Ni(0) and Gd(OTf)3.8
To optimize the reaction conditions, we first studied the
effects of ligands on Ni using enone 1s as a model sub-
strate (Table 1). In the absence of any additive ligand,
product 3s was obtained in ca. 80% yield using 20 mol%
of Ni(cod)2 at 70 °C in THF for 11 hours (entry 1). Using
10 mol% of the catalyst, however, results were not stable;
the reaction did not complete in most cases even after pro-
Substrate scope was examined under the optimized condi-
tions (Table 3). In all cases studied, the acceleration effect
of Gd(OTf)3 was remarkable (entries 1–6, 8–11).9 The re-
action time was significantly decreased, and the products
were afforded in high yields. Specifically, in the case of a
substrate for quaternary carbon synthesis (1e) and phenyl
SYNLETT 2008, No. 15, pp 2295–2298
1
5
.0
9
.2
0
0
8
Advanced online publication: 21.08.2008
DOI: 10.1055/s-2008-1078264; Art ID: U05708ST
© Georg Thieme Verlag Stuttgart · New York

2296
Y. Tanaka et al.
LETTER
Table 2 Optimization of the Reaction Conditions: Effects of Lewis
Table 3 Catalytic Conjugate Addition of Cyanide to Enones Using
Acid Co-Catalyst
Ni and Gd(OTf)3
1) Ni(cod)2 (x mol%)
[Lewis acid (x mol%)]
nbd (3x mol%)
cyanide (1.5 equiv)
THF, r.t., 4 h
Ni(cod)2 (x mol%), nbd (3x mol%)
Gd(OTf)3 (x mol )
TBSCN (1.5 equiv)
R4
O
R4
OSiR2R'
O
O
R3
NC
R1
R3
R1
THF, r.t.
R2
R2
2) H+
NC
3
1
2e
1e
Entry Substrate
x
Time Yield
Yield (%)a
(mol%) (h)
(%)a
Entry
Catalyst load- Lewis acid
ing (x)
Cyanide
1b
1a: n = 0
5
2
2
2
5
5
5
19
3
4
24c
88
77c
89
8c
1b
2
5
10
10
10
10
10
10
5
–
TMSCN
TMSCN
TMSCN
TMSCN
TMSCN
TMSCN
TBSCN
TBSCN
TBSCN
0
O
2
1a: n = 0
1b: n = 1
1b: n = 1
1c: n = 2
1c: n = 2
1d: n = 3
3b
4
Sc(OTf)3
Y(OTf)3
La(OTf)3
Gd(OTf)3
Yb(OTf)3
Gd(OTf)3
Gd(OTf)3
Gd(OTf)3
65
86
92
94
70
91c
81c
0
1
5b
6
19
0.25
1
( )n
3
84
84
7
4
O
8b
9
1e
1e
5
5
44
4
0
81
5
6
7
10b
11
1f
1f
2
2
44
0
O
0.25
95
8
Ph
9d
5
O
12
13
1g
1h
2
2
2
3
87
90
Pr
Pr
Pr
a Isolated yield.
b Reaction time was 44 h.
O
O
c Yield as enol silyl ether by quenching the reaction with SiO2.
d In the absence of Ni catalyst.
14
15
1i
1j
2
2
4
6
94
96
ketone 1f, no reaction proceeded in the absence of
Gd(OTf)3 (entries 8 and 10). By contrast, yields were
greater than 80% in the presence of Gd(OTf)3 (entries 9
and 11). Substrate generality under the present reaction
conditions was broad, covering cyclic, aryl, and linear
enones. Catalyst loading could be reduced to 2 mol%.10 In
all entries, the reactions were completely 1,4-selective,
and 1,2-adducts were not detected.
O
O
Pr
Pr
16
17
18
1k
1l
2
2
2
4
2
1
94
88
85
Ph
O
C5H11
O
OTMS
catalyst
O
O
TMSCN
(3 equiv)
1m
NHAc
NHAc
ref. 5b
NHAc
Ph
THF
O
NHBoc
NC
NHBoc
+
EtO2C
NH3
19
1n
10
4
75
1r
3r
–
PO4
Tamiflu
(4)
Ni(cod)2 (50 mol%), cod (50 mol%)
60 °C, 3 h (previous work)5b
90%
93%
O
20
21
22
1o
1p
1q
2
2
79
49
83
Ni(cod)2 (10 mol%), nbd (30 mol%)
Gd(OTf)3 (5 mol%), r.t., 2 h (this work)
BnO
t-Bu
Ph
O
Scheme 1 Application to a key conversion in Tamiflu synthesis
2
3
The synthetic utility of this reaction was demonstrated by
applying to the conjugate cyanation of 1r, a key conver-
sion in our Tamiflu (4) synthesis.5b,11 In the previous con-
ditions in the absence of Gd(OTf)3, the conjugate
cyanation of 1r was promoted in the presence of 50 mol%
of Ni(cod)2–cod (1:1) in THF at 60 °C for three hours.
Product 3r was obtained in ca. 90% yield. By contrast, 3r
O
10
0.25
a Isolated yield.
b Using TMSCN in the absence of Gd(OTf)3.
c Yields of b-cyano ketone after quenching the reaction with 1 M HCl.
Synlett 2008, No. 15, 2295–2298 © Thieme Stuttgart · New York

LETTER
Conjugate Addition of Cyanide to Enones
2297
Ni(cod)2 (2 mol%), nbd (6 mol%)
Gd(OTf)3 (2 mol%)
open coordination site on Ni. Therefore, olefin ligands
(nbd or cod), which datively coordinate to Ni, are suitable
compared to strongly coordinating phosphine ligands.
The subsequent oxidative addition of an enone to Ni(0)
produces a p-oxa–nickel complex 7. This step is revers-
ible, and the forward reaction might be sluggish or does
not proceed in the absence of the Lewis acid co-catalyst.
On the other hand, in the presence of Gd(OTf)3, this p-
oxa–nickel formation step should be greatly accelerated
through coordination of the carbonyl oxygen atom to the
hard Lewis acid (9 and 10). Then, the generated enolate
10 is trapped with the silyl group of the cyanide source
(TMSCN or TBSCN), which proceeds concomitantly
with cyanide transfer from silicon to nickel, affording 8.
Gadolinium triflate is regenerated in this step. Reductive
elimination occurs selectively at the b-position, affording
product 3, with regeneration of the active Ni(0) catalyst.
CN OSiR2R'
TMSO
Pr
CN
TBSCN (1.5 equiv)
Pr
THF, r.t., 2 h
5
3g
Scheme 2 Experimental supports suggesting that 1,4-adducts are
kinetically controlled products
was obtained in 93% yield in the presence of 10 mol%
Ni(cod)2–nbd (1:3) and 5 mol% Gd(OTf)3 at room tem-
perature for two hours (Scheme 1). Compound 3r was
converted into 4 in six steps.5b
Although detailed studies are required to clarify the reac-
tion mechanism, the present Ni(0)- and Gd(OTf)3-cata-
lyzed reaction likely proceeds via a completely different
mechanism compared to the previous hard-metal-mediat-
ed conjugate cyanation reactions, in which the regioselec-
tivity was controlled based on the thermodynamic
stability of the 1,4-adducts compared to the 1,2-adducts.1,2
Specifically, in the present reaction, the regioselectivity is
kinetically controlled; cyanide rearrangement did not pro-
ceed at all when subjecting TMS-protected cyanohydrin 5
derived from 1g to the reaction conditions (Scheme 2).
These results sharply contrast with the previous finding
that 1,4-adducts are produced from the corresponding 1,2-
adducts via rearrangement in the presence of hard-metal-
derived reagents or catalyst.1–3
In summary, we developed a synthetically useful catalytic
conjugate addition of cyanide to enones using cooperative
catalysis of Ni(0) and Gd(OTf)3. This new method exhib-
ited a broad substrate scope. Specifically, the reaction
from enone 1r containing multiple Lewis basic sites pro-
ceeded smoothly under mild conditions, which signifi-
cantly enhanced the synthetic efficiency of Tamiflu.
Enone 1r is a totally unreactive substrate under the con-
ventional conjugate cyanation conditions using hard-met-
al cyanide as a nucleophile. The hard Lewis acid co-
catalyst, Gd(OTf)3, is thought to facilitate the catalytic cy-
cle by accelerating the oxidative addition of Ni(0) to
enones. Detailed studies to clarify the reaction mechanism
as well as extension of this platform reaction to a catalytic
asymmetric variant are currently ongoing.
Based on the above information regarding the origin of
the regioselectivity, as well as on the previously reported
reaction mechanism of Ni-catalyzed conjugate addition
reactions to enones,12 we postulate the catalytic cycle
shown in Scheme 3. First, an enone coordinates to Ni(0),
affording olefin complex 6. This initial step requires an
Scheme 3 Proposed catalytic cycle
Synlett 2008, No. 15, 2295–2298 © Thieme Stuttgart · New York

2298
Y. Tanaka et al.
LETTER
product. On the other hand, the reaction using TBSCN was
clean, yielding 92% of 3c.
Acknowledgment
Financial support was provided by Grant-in-Aid for Specifically
Promoted Research from MEXT and Grant-in-Aid for Scientific
Research (B) from JSPS. We thank Dr. T. Arai at Chiba University
and Professer Sasai at Osaka University for their contribution at the
initial stage of this project.
(8) For previous examples of Ni(0) and Lewis acid catalyzed
reactions, see: (a) Nakao, Y.; Yada, A.; Ebata, S.; Hiyama,
T. J. Am. Chem. Soc. 2007, 129, 2428. (b) Nakao, Y.;
Hirata, Y.; Tanaka, M.; Hiyama, T. Angew. Chem. Int. Ed.
2008, 47, 385. (c) Nakao, Y.; Kanyiva, K. S.; Hiyama, T.
J. Am. Chem. Soc. 2008, 130, 2448. (d) Mori, N.; Ikeda, S.;
Sato, Y. J. Am. Chem. Soc. 1999, 121, 2722. (e) Baxter, R.
D.; Montgomery, J. J. Am. Chem. Soc. 2008, 130, 9662.
(9) In the absence of Gd(OTf)3, TBSCN was not an effective
nucleophile; the yield of 3b decreased to as low as 6% using
TBSCN in the absence of Gd(OTf)3, whereas the yield was
77% using TMSCN in the absence of Gd(OTf)3 (Table 3,
entry 3).
References and Notes
(1) Nagata, W.; Yoshioka, M. Organic Reactions, Vol. 25;
Dauben, W. G., Ed.; John Wiley and Sons: New York, 1977,
255; and references cited therein.
(2) (a) Umimoto, K.; Obayashi, M.; Shishiyama, Y.; Inoue, M.;
Nozaki, H. Tetrahedron Lett. 1980, 21, 3389. (b) Umimoto,
K.; Wakabayashi, Y.; Horiie, T.; Inoue, M.; Shishiyama, Y.;
Obayashi, M.; Nozaki, H. Tetrahedron 1983, 39, 967.
(c) Kawasaki, Y.; Fujii, A.; Nakano, Y.; Sakaguchi, S.; Ishii,
K. J. Org. Chem. 1999, 64, 4214.
(3) We recently developed the first synthetically useful
enantioselective conjugate addition of cyanide to enones
using a polymetallic Gd catalyst. See: Tanaka, Y.; Kanai,
M.; Shibasaki, M. J. Am. Chem. Soc. 2008, 130, 6072.
(4) For catalytic enantioselective conjugate addition of cyanide
to a,b-unsaturated carboxylic acid derivatives, see:
(a) Sammis, G. M.; Jacobsen, E. N. J. Am. Chem. Soc. 2003,
125, 4442. (b) Sammis, G. M.; Danjo, H.; Jacobsen, E. N.
J. Am. Chem. Soc. 2004, 126, 9928. (c) Mazet, C.;
Jacobsen, E. N. Angew. Chem. Int. Ed. 2008, 47, 1762.
(d) Mita, T.; Sasaki, K.; Kanai, M.; Shibasaki, M. J. Am.
Chem. Soc. 2005, 127, 514. (e) Fujimori, I.; Mita, T.; Maki,
K.; Shiro, M.; Sato, A.; Furusho, S.; Kanai, M.; Shibasaki,
M. Tetrahedron 2007, 63, 5820. (f) Madhavan, N.; Weck,
M. Adv. Synth. Catal. 2008, 350, 419.
(5) (a) Fukuta, Y.; Mita, T.; Fukuda, N.; Kanai, M.; Shibasaki,
M. J. Am. Chem. Soc. 2006, 128, 6312. (b) Yamatsugu, K.;
Kamijo, S.; Suto, Y.; Kanai, M.; Shibasaki, M. Tetrahedron
Lett. 2007, 48, 1403.
(6) Yields of 2e using other Lewis acid co-catalysts: 13%
(TiCl4), 71% (ZnI2), 51% [Cu(OTf)2], 89% (BF3·OEt2).
(7) When using TMSCN as a nucleophile, the 1,4-addition
products, enol TMS ethers, overreacted with the starting
enones under the reaction conditions in the presence of
Gd(OTf)3 in some cases, leading to diminished yields of the
1,4-products. For example, when 2-cyclohepten-1-one (1c)
was used as a substrate, the reaction using TMSCN produced
a complex mixture, yielding only 40% of the 1,4-addition
(10) General Procedure for Ni/Gd(OTf)3-Catalyzed
Conjugate Addition of Cyanide to Enones (Table 2, entry
4)
The reaction was performed using degassed solvents under
Ar atmosphere. To a solution of Ni(cod)2 (1.7 mg, 0.006
mmol) in THF (0.2 mL), norbornadiene (1.83 mL, 0.018
mmol) was added. Gadolinium triflate (3.6 mg, 0.006 mmol)
was added to the mixture, followed by the addition of 2-
cyclohexene-1-one (1b: 29.0 mL, 0.30 mmol). Then, TBSCN
(63.6 mg, 0.45 mmol) in THF (0.1 mL) was added to start the
reaction. After stirring for 1 h, the reaction mixture was
directly loaded on SiO2 column (Caution! Highly toxic HCN
is generated in this step. This operation should be conducted
in a well-ventilated hood), and purified by flash column
chromatography (SiO2, Et2O–hexane, 1:20) to afford 3b
(62.6 mg, 0.264 mol) in 89% yield.
(11) For the latest review of Tamiflu synthesis, see: Shibasaki,
M.; Kanai, M. Eur. J. Org. Chem. 2008, 1839.
(12) (a) Grisso, B. A.; Johnson, R. J.; Mackenzie, P. B. J. Am.
Chem. Soc. 1992, 114, 5160. (b) Ikeda, S.; Sato, Y. J. Am.
Chem. Soc. 1994, 116, 5975. (c) Sieber, J. D.; Liu, S.;
Morken, J. P. J. Am. Chem. Soc. 2007, 129, 2214.
(d) Sieber, J. D.; Morken, J. P. J. Am. Chem. Soc. 2008, 130,
4978. (e) Hirano, K.; Yorimitsu, H.; Oshima, K. Org. Lett.
2007, 9, 5031. (f) Ogoshi, S.; Nagata, M.; Kurosawa, H.
J. Am. Chem. Soc. 2006, 128, 5350. (g) Chowdhury, S. K.;
Amarasinghe, K. K. D.; Heeg, M. J.; Montgomery, J. J. Am.
Chem. Soc. 2000, 122, 6775. (h) Herath, A.; Li, W.;
Montgomery, J. J. Am. Chem. Soc. 2008, 130, 469.
(i) Perez, I.; Sedtelo, J. P.; Maestro, M. A.; Mourino, A.;
Sarandeses, L. A. J. Org. Chem. 1998, 63, 10074. (j) For a
Pd–Lewis acid combination, see: Ogoshi, S.; Yoshida, T.;
Nishida, T.; Morita, M.; Kurosawa, H. J. Am. Chem. Soc.
2001, 123, 1944.
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