Nickel-catalyzed carbocyanation of alkynes with allyl cyanides

Article abstract of DOI:10.1021/ja901374v

Allyl cyanides are found to add across alkynes in the presence of a nickel/P(4-CF₃-C₆H₄)₃ catalyst to give polysubstituted 2,5-hexadienenitriles with defined stereo- and regiochemistry. Use of AlMe₂Cl or AlMe₃ as a Lewis acid cocatalyst accelerates the reaction and expands the substrate scope significantly. The cyano group in the allylcyanation products can be transformed to a hydroxymethyl or aminomethyl group to afford highly substituted allylic alcohols or amines. α-Siloxyallyl cyanides also add across alkynes selectively at the less hindered γ-carbon to allow introduction of 3-oxo-propyl functionality after hydrolysis of the resulting silyl enol ethers. This particular carbocyanation reaction has been applied to the stereoselective construction of the trisubstituted double bond of plaunotol, an antibacterial natural product active against Helicobacter pylori.

Full text of DOI:10.1021/ja901374v

Published on Web 07/16/2009
Nickel-Catalyzed Carbocyanation of Alkynes with Allyl
Cyanides
Yasuhiro Hirata, Tomoya Yukawa, Natsuko Kashihara, Yoshiaki Nakao,* and
Tamejiro Hiyama*
Department of Material Chemistry, Graduate School of Engineering, Kyoto UniVersity,
Kyoto 615-8510, Japan
Received February 22, 2009; E-mail: yoshiakinakao@npc05.mbox.media.kyoto-u.ac.jp;
thiyama@z06.mbox.media.kyoto-u.ac.jp
Abstract: Allyl cyanides are found to add across alkynes in the presence of a nickel/P(4-CF3-C6H4)3 catalyst
to give polysubstituted 2,5-hexadienenitriles with defined stereo- and regiochemistry. Use of AlMe2Cl or
AlMe3 as a Lewis acid cocatalyst accelerates the reaction and expands the substrate scope significantly.
The cyano group in the allylcyanation products can be transformed to a hydroxymethyl or aminomethyl
group to afford highly substituted allylic alcohols or amines. R-Siloxyallyl cyanides also add across alkynes
selectively at the less hindered γ-carbon to allow introduction of 3-oxo-propyl functionality after hydrolysis
of the resulting silyl enol ethers. This particular carbocyanation reaction has been applied to the
stereoselective construction of the trisubstituted double bond of plaunotol, an antibacterial natural product
active against Helicobacter pylori.
Table 1. Nickel-Catalyzed Allylcyanation of 4-Octyne (2a)a
Introduction
Development of regio- and stereoselective construction of
polysubstituted ethenes is an important issue in synthetic organic
chemistry.1 Of many synthetic methods, transition metal-
catalyzed regio- and stereoselective addition reactions across
alkynes have advanced significantly to a level of particularly
useful protocols.2 For example, allyl-functionalization reactions
such as allyl-metalation,3 allyl-halogenation,4 and allyl-chalco-
genation5 followed by C-C bond-forming reactions are power-
ful and straightforward methods to access synthetically versatile
highly substituted 1,4-diene structures. Ultimately, however,
direct insertion of alkynes into an allylic C-C bond should be
of great synthetic potential to construct such structures ef-
ficiently. Carbocyanation reactions of alkynes have appeared
recently as new efficient methods for stereo- and regioselective
construction of polysubstituted ethenes.6,7 While various nitriles
have been demonstrated to participate in the carbocyanation
reaction through oxidative addition of C-CN bonds to pal-
ladium(0) or nickel(0), allyl cyanides have been expected to be
a promising substrate for the transformation because their C-CN
bonds have also been known to undergo the oxidative addition
readily to nickel(0).8 A representative example is seen in the
DuPont adiponitrile process, which utilizes nickel-catalyzed
isomerization of 2-methyl-3-butenenitrile to 3- and 4-penteneni-
triles through oxidative addition of the C-CN bond to
nickel(0).9 A π-allylnickel intermediate generated by the oxida-
tive addition is suggested to undergo reductive elimination at
the less hindered carbon to give linear 3-pentenenitrile, which
is subjected to hydrocyanation to give finally adiponitrile.
Accordingly, we envisaged that insertion of alkynes into the
entry
ligand
solvent
yield of 3aa (%)b
1c
2e
3
4
5
6
7
8
9
P(4-CF3-C6H4)3
P(4-CF3-C6H4)3
P(4-CF3-C6H4)3
P(4-CF3-C6H4)3
P(4-CF3-C6H4)3
PPh3
CH3CN
CH3CN
DMF
1,4-dioxane
toluene
CH3CN
CH3CN
CH3CN
CH3CN
98 (78)d
35
70
39
22
61
8
P(4-MeO-C6H4)3
PMe3
0
2
P(OPh)3
a All reactions were carried out using 1a (0.80 mmol), 2a (0.20
mmol), Ni(cod)2 (20 µmol), and ligand (40 µmol) in a solvent (0.40
mL) at 80 °C for 8 h. b Estimated by GC using C14H30 as an internal
standard. c The reaction was carried out using 1a (4.0 mmol) and 2a
(1.00 mmol). d Isolated yield based on 2a. e The reaction was carried out
using 1a (0.20 mmol) and 2a (0.20 mmol).
allyl-Ni bond of the π-allyl nickel intermediate10 followed by
reductive elimination could lead to catalytic allylcyanation
reaction of alkynes. Herein we describe nickel- or nickel/Lewis
acid-catalyzed regio- and stereoselective carbocyanation of
alkynes with allyl cyanides to afford highly functionalized
polysubstituted acrylonitriles with a variety of functional
groups.11 We also demonstrate the synthetic utility of the
carbocyanation reaction by efficient synthesis of a trisubstituted
ethene moiety of plaunotol, an antibacterial particularly effective
against Helicobacter pylori.
Results and Discussion
(1) (a) Faulkner, J. Synthesis 1971, 175–189. (b) Flynn, A. B.; Ogilvie,
W. W. Chem. ReV. 2007, 107, 4698–4745.
Nickel-Catalyzed Allylcyanation of Alkynes. We first exam-
ined the reaction of allyl cyanide (1a, 4.0 mmol) with 4-octyne
(2) ComprehensiVe Organometallic Chemistry III; Crabtree, R. H.; Mingos,
D. M. P.; Ojima, I., Eds.; Elsevier: Oxford, 2007, Vol. 10.
9
10964 J. AM. CHEM. SOC. 2009, 131, 10964–10973
10.1021/ja901374v CCC: $40.75  2009 American Chemical Society

Stereo- and Regioselective Allylcyanation of Alkynes
A R T I C L E S
Table 2. Allylcyanation of 4-Octyne (2a) Using Substituted Allyl Cyanides Catalyzed by Nickela
a All reactions were carried out using a nitrile (4.0 mmol), 2a (1.00 mmol), Ni(cod)2 (0.100 mmol), and P(4-CF3-C6H4)3 (0.20 mmol) in CH3CN (2.0
c
mL) at 80 °C. b Isolated yields based on 2a. Estimated by H NMR and/or GC analysis of a crude and/or purified product. d The reaction was carried
1
out in CH3CN (1.0 mL).
1
(2a, 1.0 mmol) in acetonitrile at 80 °C in the presence of
Ni(cod)2 (10 mol %) and various phosphine ligands (Table 1).
Of ligands examined, P(4-CF3-C6H4)3 (20 mol %) was found
to be the most effective to give (Z)-2,3-dipropylhexa-2,5-
dienenitrile (3aa) in 78% yield after isolation (entry 1). The
stereochemistry was unambiguously assigned by NOE experi-
ments irradiating the allylic methylenes in H NMR analyses.
An equimolar reaction resulted in a low yield of 3aa due
presumably to formation of unidentified side products derived
from side reactions of allyl cyanide (entry 2). Phosphorus ligands
having electron-donating substituents and phosphites as well
as use of less polar solvents all retarded the reaction (entries
3-9).
With the optimized conditions in hand, we next examined
the scope of the reaction (Table 2 and eq 1). Carbocyanation of
2a with both 3-pentenenitrile (1b) and 2-methyl-3-butenenitrile
(1c) gave the same crotylcyanation product (3ba) as a mixture
of stereoisomers in similar yields with similar stereoselectivity
(entries 1 and 2). No trace amount of an R-adduct was obtained
with 1c, suggesting a catalytic cycle involving a π-crotylnickel
intermediate (Vide infra). The reactions of (E)-5,5-dimethyl-3-
hexenenitrile (1d) and (E)-4-phenyl-3-butenenitrile (1e) gave
the corresponding R-adducts as single stereoisomers possibly
through a syn-π-allylnickel species (entries 3 and 4). The
addition of cyclopenten-1-ylacetonitrile (1f) was sluggish (entry
5). The allylcyanation of 1-phenyl-1-propyne (2b) with 1a gave
a mixture of two regioisomers (3ab/3′ab ) 94:6) in 43% yield
(eq 1). An isomer having a phenyl group at the cyano-substituted
carbon was obtained as a major product. The regiochemistry
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H.; Oshima, K. Synlett 2004, 1573–1574. (q) Allylindation: Araki, S.;
Imai, A.; Shimizu, K.; Butsugan, Y. Tetrahedron Lett. 1992, 33, 2581–
2582. (r) Araki, S.; Imai, A.; Shimizu, K.; Yamada, M.; Mori, A.;
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Bäckvall, J.-E.; Nilsson, Y. I. M.; Gatti, R. G. P. Organometallics
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A R T I C L E S
Hirata et al.
Table 3. Carbocyanation of 4-Octyne (2a) Using R-Siloxyallyl Cyanides Catalyzed by Nickela
a All reactions were carried out using a nitrile (1.50 mmol), 2a (1.0 mmol), Ni(cod)2 (0.100 mmol), and P(4-CF3-C6H4)3 (0.20 mmol) in CH3CN (1.0
mL), and crude products were treated with 1 M HCl aq in THF at 0 °C to rt. b Isolated yields based on 2a. c 5E/5Z ) 52:48. d 5E/5Z ) 22:78.
carbocyanation reaction (Table 3).12 Worth noting is that 1g
(1.5 mmol) reacted with 2a exclusively at the γ-carbon of 1g
to give aldehyde 3ga in 81% yield after hydrolysis of the
resulting silyl enol ether (entry 1). The reactions of R-tert-
butyldimethylsiloxyallyl cyanide (1h) and R-methoxyallyl cya-
nide (1i) with 2a gave the corresponding enol ether products,
which were successfully isolated by silica gel column chroma-
tography as a mixture of stereoisomers (entries 2 and 3). Silyl
ethers of enone cyanohydrins also reacted similarly at 120 °C
to give the corresponding cyanoketones (entries 4-6). Whereas
a ꢀ-substituent in 1m did not affect the reaction to give aldehyde
3ma in good yield at 80 °C (entry 7), γ-substituted R-siloxyallyl
cyanide 1n did not participate in the reaction (entry 8).
1
was unambiguously assigned by H NMR NOE experiments.
On the other hand, reactions with terminal alkynes such as
1-octyne gave no detectable amount of allylcyanation products
due to rapid trimerization and/or oligomerization of the alkynes.
Nickel-Catalyzed Carbocyanation of Alkynes Using r-Si-
loxyallyl Cyanides. R-Siloxyallyl cyanide (1g), readily available
from acrolein and trimethylsilyl cyanide, also underwent the
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Stereo- and Regioselective Allylcyanation of Alkynes
A R T I C L E S
Table 4. Carbocyanation of Internal Alkynes Using 1g Catalyzed by Nickela
a All reactions were carried out using 1g (1.50 mmol), an alkyne (1.0 mmol), Ni(cod)2 (0.100 mmol), and P(4-CF3-C6H4)3 (0.20 mmol) in CH3CN
(1.0 mL) at 80 °C for 1 h, and crude products were treated with 1 M HCl aq in THF at 0 °C to rt. b Isolated yields of an inseparable mixture of two
c
1
regioisomers based on 2. Determined by H NMR and/or GC analysis of a crude and/or purified product.
Various internal alkynes were examined next for the
reaction with 1g (Table 4). The addition of 1g across 2b
proceeded in good yield with high regioselectivity (entry 1).
Moderate yield of 3gc was obtained with 2-butyne (2c) due
presumably to competitive trimerization and/or oligomeriza-
tion of 2c under the reaction conditions (entry 2). Poor or
no regioselection was observed with alkynes having sterically
similar substituents 2d-2f (entries 3-5) even with a tethered
olefin moiety (entries 4 and 5).13 Alternatively, heteroatoms
such as oxygen and nitrogen at a propargylic position of
alkynes were found to effect regioselection of the carbocya-
nation (entries 6-9). Remarkably, the effect was further
intensified by introducing an allyl group on the propargylic
heteroatoms (entry 6 vs entry 7 and entry 8 vs entry 10),
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A R T I C L E S
Hirata et al.
Table 5. Allylcyanation of Terminal Alkynes Using 1g Catalyzed by Nickela
a All reactions were carried out using 1g (1.00 mmol), an alkyne (2.0 mmol), Ni(cod)2 (0.100 mmol), and P(4-CF3-C6H4)3 (0.20 mmol) in CH3CN
(1.0 mL) at 80 °C for 1 h, and crude products were treated with 1 M HCl aq in THF at 0 °C to rt. b Isolated yields of an inseparable mixture of two
c
regioisomers based on 1g. Determined by H NMR and/or GC analysis of a crude and/or purified product. d The reaction was carried out using 1g (15
1
mmol) and 2l (30 mmol).
whereas a possibly chelating methoxymethyl ether moiety
gave no significant improvement of the regioselectivity
compared with the methyl ether (entry 9 vs entry 10).
Gratifyingly, 1g underwent the carbocyanation reaction across
terminal alkynes in modest to good yields (Table 5). To push
the reaction effectively as compared with rapid cyclotrimeriza-
tion and/or oligomerization of terminal alkynes, use of 2 mol
equiv of terminal alkynes is preferred. The reactions were
smooth and regioselective like the ones with internal alkynes;
adducts having substituents at a cyano-substituted carbon were
major products. The reaction tolerated a gram-scale synthesis
(entry 1). Excellent regioselectivity was observed with alkynes
having a bulky substituent such as t-Bu and SiMe3 (entries 3
and 4). Highly substituted allylsilane 3gp was obtained from
propargylsilane 2p in good yield (entry 5). Terminal alkynes
having various functional groups including chloro, ester, and
N-phthalimidoyl underwent the reaction to give the correspond-
ing substituted acrylonitriles in good yields (entries 6-8),
whereas methyl or tert-butyldimethylsilyl propargyl ethers gave
rise to no trace amount of the corresponding adducts but trimers
of the alkynes.
Allylcyanation of Alkynes Catalyzed by Nickel/Lewis Acid.
It has recently been reported that the arylcyanation of alkynes
is significantly accelerated by a Lewis acid cocatalyst.6f The
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Stereo- and Regioselective Allylcyanation of Alkynes
A R T I C L E S
Table 6. Effect of Lewis Acid Cocatalysts on the Reaction of 1a
with 2aa
2a, AlMe2Cl (6 mol %) was found to be optimum to give 3aa
in 96% yield even using allyl cyanide (1a) and 4-octyne (2a)
in stoichiometric amounts and the nickel catalyst in a small
amount (2 mol %) (entry 2 of Table 6). AlMe3, AlMeCl2, and
BPh3 were not as effective as AlMe2Cl (entries 1, 3, and 4),
whereas the absence of Lewis acid gave only a trace amount of
3aa under the modified conditions (entry 5). Use of polar
solvents such as acetonitrile, 1,4-dioxane, and DMF was futile
with this binary catalyst system.
With the nickel/AlMe2Cl catalyst in hand, we reexamined
the scope of the allylcyanation reaction (Table 7). Substituted
allyl cyanides 1e and 1f underwent the equimolar reaction
with 2a with 2 mol % of the nickel catalyst at 50 °C (entries
1 and 2). γ,γ-Disubstituted allyl cyanide such as prenyl
cyanide (1o), which was inert under the conditions without
a Lewis acid cocatalyst, participated in the reaction (entry
3). The scope of alkynes with 1a as a nitrile substrate was
significantly expanded to include various terminal alkynes
(entries 4-10). Complete regioselectivity observed with
terminal alkynes is particularly useful for synthesis of
trisubstituted ethenes (entries 5-10). Functional groups such
as chloro, cyano, and siloxy did not affect the Lewis acid
cocatalysis (entries 8-10).
entry
Lewis acid
yield (%)b
1
2
3
4
5
AlMe3
AlMe2Cl
AlMeCl2
BPh3
6
96c
51
39
2
none
a All reactions were carried out using 1a (1.00 mmol), 2a (1.00
mmol), Ni(cod)2 (20 µmol), P(4-CF3-C6H4)3 (40 µmol), and Lewis acid
(60 µmol) in toluene (1.00 mL) at 50 °C for 24 h. b Determined by GC
using C14H30 as an internal standard. c Isolated yield.
effect of BPh3 as a Lewis acid on the oxidative addition of allyl
cyanides to a nickel(0)/bisphosphine complex has also been
revealed in detail by Jones, making the elemental reaction
preferable kinetically and thermodynamically compared with
competitive oxidative addition of the allylic C-H bond.8b
Because unidentified side reactions of allyl cyanide 1a could
be ascribed to this competitive pathway and thus use of 1a in
excess was essential to obtain allylcyanation products in good
yields, we anticipated that use of a Lewis acid cocatalyst would
be beneficial for the allylcyanation reaction especially with 1a.
Of Lewis acid cocatalysts examined for the reaction of 1a with
The reaction of 1p having two allylic cyanide moieties with
2 mol equiv of 2a gave double allylcyanation products 3pa and
3′pa with BPh3 as a Lewis acid cocatalyst (eq 2). Use of optimal
AlMe2Cl, on the other hand, resulted in a low conversion of 2a
(∼20%). Isomerization of the double bond geometry in 1p under
the reaction conditions was observed and would be responsible
for the formation of 3′pa.
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The binary catalysis was found also effective for the
carbocyanation reaction using R-siloxyallyl cyanide (Table
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A. R. Tetrahedron Lett. 2002, 43, 9703–9706.
(8) (a) Chaumonnot, A.; Lamy, F.; Sabo-Etienne, S.; Donnadieu, B.;
Chaudret, B.; Barthelat, J.-C.; Galland, J.-C. Organometallics 2004,
23, 3363–3365. (b) Brunkan, N. M.; Brestensky, D. M.; Jones, W. D.
J. Am. Chem. Soc. 2004, 126, 3627–3641. (c) van der Vlugt, J. I.;
Hewat, A. C.; Neto, S.; Sablong, R.; Mills, A. M.; Lutz, M.; Spek,
A. L.; Mu¨ller, C.; Vogt, D. AdV. Synth. Catal. 2004, 346, 993–1003.
(d) Wilting, J.; Mu¨ller, C.; Hewat, A. C.; Ellis, D. D.; Tooke, D. M.;
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Ram´ırez, A.; Flores-Gaspar, A.; Mun˜oz-Herna´ndez, M.; Are´valo, A.;
Jones, W. D.; Garc´ıa, J. J. Organometallics 2007, 26, 1712–1720. (f)
Acosta-Ram´ırez, A.; Mun˜oz-Herna´ndez, M.; Jones, W. D.; Garc´ıa,
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A R T I C L E S
Hirata et al.
Table 7. Nickel/Lewis Acid-catalyzed Allylcyanation of Alkynesa
a All reactions were carried out using allyl cyanide (1.00 mmol), an alkyne (1.00 mmol), Ni(cod)2 (20 µmol), P(4-CF3-C6H4)3 (40 µmol), and
AlMe2Cl (60 µmol) in toluene (2.0 mL) at 50 °C. b Isolated yields. c Determined by 1H NMR analysis. d Ni(cod)2 (0.20 mmol), P(4-CF3-C6H4)3 (0.40
mmol), and AlMe2Cl (0.60 mmol) were used. e Isolated yield of an inseparable mixture of 3ab and 3′ab.
3ga in 80% yield after acidic hydrolysis of the resulting silyl
enol ether (entry 1). Use of AlMe2Cl was less effective with
this particular nitrile substrate. To our regret, no appreciable
improvement of the stereoisomeric ratio of silyl enol ethers
formed in situ was observed by GC analyses of the reaction
mixture. Nevertheless, variously functionalized R,ꢀ-disub-
stituted acrylonitriles were obtained with excellent regiose-
lectivity higher than that observed under the conditions
without the LA catalyst (entries 2-5).
Mechanism of Allylcyanation Reaction. Catalytic cycle of
the present carbocyanation reaction should be initiated by
coordination of the double bond of allyl cyanides to nickel(0)
to give 4 or 5 followed by oxidative addition of the C-CN
bond to nickel(0) to give π-allylnickel intermediate 6 or 7
(Scheme 1).8 The intermediacy of the π-allylnickel species
6 and 7 is fully supported by literature precedents as well as
the experimental results for the reactions of crotyl and
3-buten-2-yl cyanides (entries 1 and 2 of Table 2). With
γ-substituted allyl cyanides, the resulting π-allylnickel 7
would be in equilibrium with 6 through isomerization via a
σ-allyl complex and rotation. One of the phosphine ligands
in 6 or 7 may be dissociatively substituted by an alkyne to
give 8. Migratory insertion of alkynes into the allyl-Ni bond
in 8 would take place to make bonds at the nickel-bound
less hindered allyl and alkyne carbons, giving 10 with high
regioselectivity as observed especially with alkynes having
sterically biased substituents. High regioselectivity attained
with substrates containing a propargylic heteroatom (entries
6-10 of Table 4) may be ascribed to the formation of
σ-allylnickel 9 by intramolecular coordination of a heteroatom
to the nickel center. Facile isomerization of a η3-allyl ligand
to a η1-allyl one may direct this particular coordination of
the alkynes. An allyl substituent on the heteroatom appears
to further enhance the directing effect. Reductive elimination
of alkenylnickel intermediate 10 gives cis-allylcyanation
products and regenerates nickel(0). With R-siloxyallyl cya-
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Stereo- and Regioselective Allylcyanation of Alkynes
A R T I C L E S
Table 8. Nickel/Lewis Acid-Catalyzed Carbocyanation of Alkynes
Using 1ga
Scheme 2. Oxidative Addition of Allylic C-CN vs C-H Bonds to
Nickel(0)8b
entry
alkyne (2)
time (h)
product(s)
yield (%)b (3:3′)c
1d
2
2a
2l
2p
2q
2r
12
2
7
1
2
3ga
3gl + 3′gl
3gp
3gq + 3′gq
3gr + 3′gr
80
62 (98:2)
58 (>99:1)
60 (98:2)
59 (97:3)
3e
4
5
a All reactions were carried out using 1g (1.00 mmol), an alkyne
(1.00 mmol), Ni(cod)2 (50 µmol), P(4-CF3-C6H4)3 (0.100 mmol), and
AlMe3 (0.20 mmol) in toluene (1.5 mL) at 50 °C. b Isolated yields of an
inseparable mixture of two regioisomers. c Determined by 1H NMR
analysis. d Ni(cod)2 (20 µmol), P(4-CF3-C6H4)3 (40 µmol), and
AlMe2Cl (80 µmol) were used. e 2p (3.0 mmol) was used.
Scheme 3. Transformations of Allylcyanation Productsa
nides, undesired side reactions derived possibly from allylic
C-H oxidative addition through transition state 12 (Scheme
2)8b are likely suppressed by coordination of the oxygen to
the nickel center in 14. The pronounced effect of phosphine
ligands with highly electron-withdrawing aryl groups in the
present allylcyanation reaction contrasts sharply with other
nickel-catalyzed carbocyanation reactions wherein phosphine
ligands with electron-donating alkyl groups are favored in
general.6 The oxidative addition of allyl cyanides to nickel(0)
is probably very fast compared with other nitriles, and thus,
the turnover-limiting step may lie in other elemental steps.
Especially, reductive elimination forming alkenyl-CN bonds
would be facilitated by phosphine ligands with a large
π-accepting character. Accordingly, Lewis acid cocatalysts
may also accelerate the reductive elimination,14 ligand
substitution, and/or migratory insertion of alkynes as well
as oxidative addition of allyl cyanides.8b,15
Transformations of Allylcyanation Products. Synthetic utility
of the allylcyanation products was briefly examined and is
summarized in Scheme 3. The cyano group in 3aa was reduced
to give the corresponding enal 15 and then allylic alcohol 16.
Highly substituted allylamine 17 was also available from 3aa.
The formyl group in 3ga was reduced or methylenated16 to give
a Reagents and conditions: (a) DIBAL-H, toluene, -78 °C, 1.5 h,
then SiO2; (b) LiAlH4, THF, rt, 10 min; (c) DIBAL-H, toluene, -78
°C, 1.5 h, then NaBH4, MeOH, 0 °C, 30 min; (d) NaBH4, MeOH, 0 °C,
1 h; (e) IZnCH2ZnI, THF, rt, 30 min; (f) HCHO aq, pyrrolidine, EtCO2H,
i-PrOH, 45 °C, 24 h.
Scheme 1. Plausible Mechanism of Allylcyanation of Alkynes
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J. AM. CHEM. SOC. VOL. 131, NO. 31, 2009 10971

A R T I C L E S
Hirata et al.
Scheme 4. Total Synthesis of Plaunotola
a Reagents and conditions: (a) Ni(cod)2 (2 mol %), P(4-CF3-C6H4)3 (4 mol %), AlMe3 (8 mol %), toluene, 35 °C, 8 h, then 1 M HCl aq, THF, 0 °C to
rt; (b) Me(CO)C(N2)P(O)(OMe)2 (21), 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, 28 (5 mol %), MAO (5 mol %), rt, 48 h, then n-BuLi, (HCHO)n, THF, rt, 1.5 h; (g) TBAF, THF, rt,
12 h.
alcohol 18 and 1,5-dienenitrile 19, the latter serving as a formal
homoallycyanation product. R-Methylenation of 3ga proceeded
through aldol-type condensation to give R-substituted propenal
20 without affecting the configuration of the original CdC
bond.17
carbonyl functionalities. Finally, the reaction was applied to the
synthesis of the trisubstituted double bond in plaunotol in a high
regio- and stereoselective manner.
Acknowledgment. We thank Prof. Seijiro Matsubara for helpful
suggestions and generous donation of CH2(ZnI)2. We are also
grateful to Professor Timothy F. Jamison for fruitful discussion
and to Mr. Shinichi Oda and Mr. Jun Satoh for experimental
elaboration at the initial stage. This work has been supported
financially by a Grant-in-Aid for Creative Scientific Research, COE
Research on “Elements Science” and on “United Approach to New
Material Science”, and Priority Areas “Molecular Theory for Real
Systems” from MEXT. Y.H. acknowledges the JSPS for a predoctoral
The carbocyanation of terminal alkynes with R-siloxyallyl
cyanide 1g was successfully applied to regio- and stereose-
lective construction of one of the trisubstituted double bonds
in plaunotol (27), an antibacterial natural product active
against Helicobacter pylori (Scheme 4).18,19 Nickel/AlMe3-
catalyzed cis-carbocyanation of terminal alkyne 2v with 1g
proceeded at 35 °C with excellent stereo- and regioselectivity
to give aldehyde 3gv upon acidic hydrolysis in 64% yield in
a gram scale, two internal double bonds being completely
intact under the reaction conditions. The formyl group of
3gv and its regioisomer 3′gv (not shown, at most 4%) was
transformed to terminal alkyne 22 by the Ohira-Bestmann
protocol.20 The isomer derived from 3′gv was readily
removed at this stage by silica gel column chromatography.
The cyano group was reduced to give substituted allylic
alcohol 24 through aldehyde 23 with complete retention of
its stereochemistry. The hydroxy group was protected with
TIPS-Cl, and the terminal alkyne moiety was subjected to
the regio- and stereoselective Negishi methylalumination
reaction according to a modified protocol reported by
Lipshutz using 28 as a catalyst21,22 to construct another
trisubstituted double bond upon treatment of the resulting
alkenylaluminum species with paraformaldehyde all in one
pot. Deprotection of the TIPS group gave plaunotol (27).
(14) Huang, J.; Haar, C. M.; Nolan, S. P.; Marcone, J. E.; Moloy, K. G.
Organometallics 1999, 18, 297–299.
(15) (a) Tolman, C. A.; Seidel, W. C.; Druliner, J. D.; Domaille, P. J.
Organometallics 1984, 3, 33–38. (b) McKinney, R. J. Organometallics
1985, 4, 1142–1143. (c) McKinney, R. J.; Nugent, W. A. Organo-
metallics 1989, 8, 2871–2875.
(16) Matsubara, S. In Hand Book of Functionalized Organometallics;
Knochel, P., Ed.; Wiley-VCH: Weinheim, 2005; pp 347-377.
(17) Erkkila¨, A.; Pihko, P. M. J. Org. Chem. 2006, 71, 2538–2541.
(18) (a) Ogiso, A.; Kitazawa, E.; Kurabayashi, M.; Sato, A.; Takahashi,
S.; Noguchi, H.; Kuwano, H.; Kobayashi, S.; Mishima, H. Chem.
Pharm. Bull. 1978, 26, 3117–3123. (b) Koga, T.; Kawada, H.; Utsui,
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K.; Utsui, Y.; Domon, H.; Ishii, C.; Narita, T.; Yasuda, H. J.
Antimicrob. Chemother. 1998, 42, 133–140.
(19) Examples of total synthesis of plaunotol: (a) Sato, K.; Miyamoto, O.;
Inoue, S.; Kobayashi, T.; Furusawa, F. Chem. Lett. 1981, 1711–1714.
(b) Sato, K.; Miyamoto, O.; Inoue, S.; Iwase, N.; Honda, K. Chem.
Lett. 1988, 1433–1436. (c) Inoue, S.; Honda, K.; Iwase, N.; Sato, K.
Bull. Chem. Soc. Jpn. 1990, 63, 1629–1635. (d) Takayanagi, H.
Tetrahedron Lett. 1994, 35, 1581–1584. (e) Fujiwara, T.; Tsuruta, Y.;
Takeda, T. Tetrahedron Lett. 1995, 36, 8435–8438. (f) Honda, K.;
Igarashi, D.; Asami, M.; Inoue, S. Synlett 1998, 685–687. (g) Tago,
K.; Arai, M.; Kogen, H. J. Chem. Soc., Perkin Trans. 1 2000, 2073–
2078. (h) Tago, K.; Kogen, H. Tetrahedron 2000, 56, 8825–8831. (i)
Li, W.-D. Z.; Peng, Y. Org. Lett. 2005, 7, 3069–3072.
Conclusion
In summary, stereo- and regioselective allylcyanation of
alkynes has been demonstrated with a Ni(cod)2/P(4-CF3-C6H4)3
catalyst to give highly substituted and functionalized 1,4-
dienenitriles. R-Siloxyallyl cyanides are also shown to participate
in the transformation, allowing simultaneous introduction of a
cyano and 3-oxo-propyl units. Use of Lewis acid cocatalysts
significantly improves the reaction efficiency by reducing
catalyst loading, achieving stoichiometric reaction, and expand-
ing substrate scope. The resulting adducts have been shown to
undergo various transformations based on cyano, allyl, and
(20) (a) Ohira, S. Synth. Commun. 1989, 19, 561–564. (b) Mu¨ller, S.;
Liepold, B.; Roth, G. J.; Bestmann, H. J. Synlett 1996, 521–522.
(21) (a) van Horn, D. E.; Negishi, E. J. Am. Chem. Soc. 1978, 100, 2252–
2254. (b) Lipshutz, B. H.; Butler, T.; Lower, A. J. Am. Chem. Soc.
2006, 128, 15396–15398.
(22) (a) Wild, W. P.; Zsolnai, L.; Huttner, G.; Brintzinger, H. H. J.
Organomet. Chem. 1982, 232, 233–247. (b) Wild, F. W. R. P.;
Wasiucionek, M.; Huttner, G.; Brintzinger, H. H. J. Organomet. Chem.
1985, 288, 63–67.
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Stereo- and Regioselective Allylcyanation of Alkynes
A R T I C L E S
fellowship. Y.N. acknowledges the NIPPON SHOKUBAI Award in
Synthetic Organic Chemistry, Japan, Mitsubishi Chemical Corporation
Fund, NOVARTIS Foundation (Japan) for the Promotion of Science,
Japan Chemical Innovation Institute, Showa Shell Sekiyu Foundation
for Promotion of Environmental Research, The Sumitomo Foundation,
and The Uehara Memorial Foundation for supports.
Supporting Information Available: Detailed experimental
procedures including spectroscopic and analytical data. This
material is available free of charge via the Internet at http://
pubs.acs.org.
JA901374V
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