Nickel/BPh3-catalyzed alkynylcyanation of alkynes and 1,2-dienes: An efficient route to highly functionalized conjugated enynes

Article abstract of DOI:10.1002/anie.200704095

(Chemical Equation Presented) Adding across: A C(sp)-C(sp) bond of alkynyl cyanides is activated by nickel/Lewis acid catalysis derived from [Ni(cod) ₂] and BPh₃, and the alkynylcyanation reaction of alkynes and 1,2-dienes is achieve

Full text of DOI:10.1002/anie.200704095

Angewandte
Chemie
DOI: 10.1002/anie.200704095
Enyne Synthesis
Nickel/BPh3-Catalyzed Alkynylcyanation of Alkynes and 1,2-Dienes:
An Efficient Route to Highly Functionalized Conjugated Enynes**
Yoshiaki Nakao,* Yasuhiro Hirata, Masaaki Tanaka, and Tamejiro Hiyama*
In memory of Makoto Kumada
Highly substituted conjugated enynes with functional
groups have gained significant importance as versatile
synthetic intermediates.[1] However, conventional
approaches to these structures have relied on tedious
multistep sequences involving the Sonogashira cou-
pling reaction. Transition-metal-catalyzed alkynylme-
talation reactions have emerged recently as novel
protocols for the construction of conjugated enyne
À
frameworks through cleavage of a C(sp) m bond (m =
SnBu3 and B(pinacol)[3] followed by addition of the
[2]
resulting alkynyl and metallic moieties across alkynes;
the latter is then converted further to an organic group
by subsequent cross-coupling reactions. On the other hand, to
our knowledge, catalytic direct insertion of alkynes into a
We then further tested the catalysis on the reactions of
various alkynyl cyanides and found that aryl-, alkenyl-, alkyl-,
and silyl-substituted ethynyl cyanides underwent the alkynyl-
cyation reaction across 2a (entries 1–6, Table 1). In particular,
the addition of silylethynyl cyanides gave the corresponding
enynes in excellent yields even with a diminished amount of
the catalysts, presumably because the bulky silyl group
protects the triple bond and, thus, suppresses cyclotrimeriza-
tion and/or oligomerization of the nitriles (entries 5 and 6,
Table 1). It is worth noting that diynyl cyanide 1h also added
across 2a to afford functionalized conjugated endiyne 3ha in
72% yield (entry 7, Table 1). The scope of terminal alkynes in
reactions with 1g as the nitrile substrate was also studied
(entries 8–12, Table 1). The present reaction displayed excel-
lent chemoselectivity in the presence of a variety of functional
groups (entries 9–12, Table 1). An alkyl–CN bond, which is
cleavable under nickel/LA catalysis,[5] is compatible (entry 10,
Table 1). The observed regioselectivities were fair to excellent
and identical to what had been observed for the carbocyana-
tion reaction of alkynes with other nitriles;[5,7] the major
product was always the isomer having the larger substituent at
the cyano-substituted carbon.
À
C(sp) C bond has never been achieved. Herein, we report
nickel/BPh3-catalyzed alkynylcyanation of alkynes and 1,2-
dienes as an atom-economical and stereoselective method to
access functionalized conjugated enyne structures.
At the onset, we anticipated the reaction mode of alkynyl
cyanides in the presence of a nickel catalyst, because electron-
deficient alkynes are prone to undergo homo- and/or cross-
cyclotrimerization reactions under nickel catalysis.[4] Indeed,
the reaction of 3-phenylpropynenitrile (1a) with 4-octyne
(2a) in the presence of [Ni(cod)2] (10 mol%) (cod = cyclo-
octadiene) and xantphos (10 mol%) in toluene at 1008C for
3 h gave the expected cis-alkynylcyanation product (3aa) in
only 11% yield and a mixture of substituted benzenes in 66%
yield which arose by trimerization of 1a [Eq. (1)]. On the
other hand, the presence of BPh3 (30 mol%) as a Lewis acid
(LA) cocatalyst[5] dramatically shifted the reaction path,[6]
affording 3aa in 69% yield with a small amount of the
benzene derivatives.
Alkynyl cyanides were also found to add across 1,2-dienes
in the presence of the same catalyst (Table 2). The reaction
with alkyl-substituted allenes took place mainly at the
internal double bond, giving conjugated enynes 5 (entries 1–
[*] Dr. Y. Nakao, Y. Hirata, M. Tanaka, Prof. Dr. T. Hiyama
Department ofMaterial Chemistry, Graduate School ofEngineering
Kyoto University, Kyoto 615-8510 (Japan)
Fax: (+81)75-383-2445
[8]
E-mail: nakao@npc05.kuic.kyoto-u.ac.jp
thiyama@npc05.kuic.kyoto-u.ac.jp
4, Table 2). On the other hand, silylallene 4e showed
opposite regioselectivity, giving exclusively the Z vinylsilane
having a conjugated enyne structure (entry 5, Table 2).
The present alkynylcyanation reaction should be initiated
by the oxidative addition of a C(sp)-CN bond to nickel(0) by
the aid of BPh3 (Scheme 1).[5,9,10] An alkyne coordinates to the
nickel center, and the alkynyl group migrates to the less
hindered carbon of the coordinating alkyne to give an
alkenylnickel intermediate, which then produces conjugated
enyne 3 upon reductive elimination. On the other hand,
[**] This work has been supported financially by a Grant-in-Aid for
Creative Scientific Research (No. 16GS0209) and the Priority Area
“Molecular Theory for Real Systems” (No. 19029024) from MEXT.
Y.N. also acknowledges Japan Chemical Innovation Institute, Showa
Shell Sekiyu Foundation for Promotion of Environmental Research,
and The Sumitomo Foundation for support. Y.H. acknowledges the
JSPS for a predoctoral fellowship.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
Angew. Chem. Int. Ed. 2008, 47, 385 –387
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
385

Communications
Table 1: Nickel/BPh3-catalyzed alkynylcyanation ofalkynes.
The cyano group of the alkynyl-
cyanation products was readily con-
verted to a formyl and then to a
hydroxyalkyl group by conventional
ways with their conjugated enyne
moieties
completely
intact
(Scheme 2).[11] The resulting aldehy-
des[1c,g] and allylic alcohols[1e–h] have
been reported to serve as versatile
synthetic intermediates for a wide
range of highly substituted cyclic
compounds. On the other hand, 1,2-
diene-alkynylcyanation product 5b
was desilylated and then underwent
the stannylative cross-cycloaddition
reaction with ethyl (Z)-2-undecen-
4-ynoate in the presence of a palla-
dium-iminophosphine catalyst[1d] to
give highly substituted phenylstan-
nane 9.
Entry
1[c]
1
2
n
T [8C] t [h] Major product
yield,[a] 3/3’[b]
2a
10 100
2
2
2[c]
2a
10 80
3[c]
4[c]
5
2a
2a
2a
2a
2a
10 100
10 100
3
In conclusion, we have demon-
strated the alkynylcyanation of
alkynes and 1,2-dienes as a novel
and convenient protocol for the
3
atom-economical
synthesis
of
1
1
3
80
80
80
24
21
21
highly functionalized conjugated
enynes, which are suitable for fur-
ther inter- and intramolecular trans-
formations to elaborate a range of
carbon frameworks. Current efforts
are directed to the enantioselective
alkynylcyanation of 1,2-dienes as
well as simple olefins by the aid of
nickel/LA catalysis.
6
7
8
1g
1g
1g
1g
1
1
1
1
40
40
40
40
15
15
15
17
9
Experimental Section
General procedure for nickel/BPh3-cata-
lyzed alkynylcyanation of alkynes: An
alkynyl cyanide (1.00 mmol), an alkyne
(1.00–2.0 mmol), and C14H29 (internal
standard, 99 mg, 0.50 mmol) were
added sequentially to a solution of [Ni-
(cod)2] (2.8–28 mg, 0.010–0.10 mmol),
BPh3 (7.3–73 mg, 0.030–0.30 mmol), and
xantphos (5.8–58 mg, 0.010–0.10 mmol)
in toluene (1.5 mL) in a dry box. The vial
was taken outside the dry box and heated
at the temperature and for the time
specified in Equation (1) and Table 1.
The resulting mixture was filtered
through a silica gel pad, concentrated in
vacuo, and purified by flash column
chromatography on silica gel to give the
corresponding alkynylcyanation prod-
10
11[e]
12
1g
1
40
15
1
[a] Yield ofisolated product based on 1. [b] Estimated by H NMR analysis ofthe crude product or an
isolated mixture of 3 and 3’. [c] 2.0 mmol of 2a was used. [d] Calculated based on yield ofisolated
product. [e] 1.1 mmol of 2e was used.
coordination of a 1,2-diene takes place at its terminal double
bond, and the alkynyl group is transferred to the cumulative
ucts in the yields listed in Equation (1) and Table 1. A mixture of
regioisomers was further purified by preparative recycling silica gel
chromatography to give an isomerically pure product.
carbon of the 1,2-diene, giving a p-allylnickel species.[8]
Reductive elimination with the allyl and the cyano group
would give another type of conjugated enyne 5, although it
remains elusive how the R3 group controls the regiochemistry
of the reductive elimination.
Received: September 5, 2007
Published online: November 15, 2007
386
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Angew. Chem. Int. Ed. 2008, 47, 385 –387

Angewandte
Chemie
Table 2: Nickel/BPh3-catalyzed alkynylcyanation of1,2-dienes.
Entry
1.2-Diene
t [h]
Major product,
yield,[a] 5/5’[b]
1
2
3
19
24
17
Scheme 2. Transformations of the alkynylcyanation products. a) DIBAL-
H, toluene, À788C, 2 h, then SiO2; b) p-tolylmagnesium bromide,
=
Et2O, 08C, 2 h; c) TBAF, AcOH, THF, RT, 1 h; d) (Z)-Hex-CꢀC-CH
=
CH-CO2Et, (Bu3Sn)2O, [Cp(allyl)Pd] (5 mol%), 2-CyN CH-C6H4-PPh2
(10 mol%), THF, 508C, 24 h. Cp=C5H5, Cy=cyclohexyl, DIBAL-
H=diisobutylaluminum hydride, TBAF=tetrabutylammonium fluo-
ride.
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P.-C. Chen, R.-S. Liu, J.Am.Chem.Soc. 2006, 128, 9661; h) Y.
Liu, F. Song, S. Guo, J.Am.Chem.Soc. 2006, 128, 11332.
4
5
59
66
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[a] Yield ofisolated product. [b] Calculated based on yields ofisolated
products. [c] Estimated by 1H NMR analysis ofthe isolated mixture of 5a
and 5’a. [d] E/Z=11:89.
[4] For an example, see: a) N. Mori, S.-i. Ikeda, K. Odashima, Chem.
Commun. 2001, 181. For a review on the nickel-catalyzed
cyclotrimerization of alkynes, see: b) S. Saito in Modern
Organonickel Chemistry (Ed.: Y. Tamaru), Wiley-VCH, Wein-
heim, 2005, pp. 175 – 182.
[5] Y. Nakao, A. Yada, S. Ebata, T. Hiyama,J.Am.Chem.Soc. 2007,
129, 2428.
[6] For a related report on controlling the reaction mode of alkynes
catalyzed by nickel/Lewis acid, see: N. Mori, S.-i. Ikeda, Y. Sato,
J.Am.Chem.Soc. 1999, 121, 2722.
[7] a) Y. Nakao, S. Oda, A. Yada, T. Hiyama, Tetrahedron 2006, 62,
7567; b) Y. Nakao, T. Yukawa, Y. Hirata, S. Oda, J. Satoh, T.
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Scheme 1. A plausible mechanism for the nickel/BPh3-catalyzed alky-
[8] Cyanoesterification of 1,2-dienes also shows the same regiose-
lectivity. See: Y. Nakao, Y. Hirata, T. Hiyama, J.Am.Chem.Soc.
2006, 128, 7420.
nylcyanation.
À
À
À
[9] For the effects of Lewis acids on C CN activation by nickel(0),
Keywords: alkynes · allenes · C C activation · C C coupling ·
nickel
.
see: a) C. A. Tolman, W. C. Seidel, J. D. Druliner, P. J. Domaille,
Organometallics 1984, 3, 33; b) N. M. Brunkan, D. M. Bresten-
sky, W. D. Jones, J.Am.Chem.Soc. 2004, 126, 3627.
À
[10] Oxidative addition of the C(sp) CN bond of dicyanoacetylene
[1] For accounts, see : a) M. Rubin, A. W. Sromek, V. Gevorgyan,
Synlett 2003, 2265; b) K. Miki, S. Uemura, K. Ohe, Chem.Lett.
2005, 34, 1068; c) N. Asao, Synlett 2006, 1645. For selected recent
examples, see: d) Y. Nakao, Y. Hirata, S. Ishihara, S. Oda, T.
Yukawa, E. Shirakawa, T. Hiyama, J.Am.Chem.Soc. 2004, 126,
to platinum(0) has been reported. See: W. H. Baddley, C.
Panattoni, G. Bandoli, D. A. Clemente, U. Belluco, J.Am.Chem.
Soc. 1971, 93, 5590.
[11] For more examples, see the Supporting Information.
Angew. Chem. Int. Ed. 2008, 47, 385 –387
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